In a study of 991 adults, researchers at DZNE found that blood testing can identify the most common types of frontotemporal dementia (FTD), as well as amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). Although the procedure is not currently suitable for regular medical use, it has the potential to make disease diagnosis easier in the future.The research published in “Nature Medicine” is helping to advance the development of new therapies. The study, which involved the University Hospital Bonn and other research institutions in Germany and Spain, focused on measuring certain proteins in the blood as biomarkers. FTD, ALS, and PSP are related neurodegenerative diseases with similar symptoms, such as dementia, behavioral changes, paralysis, muscle wasting, and movement impairment. In Germany, it is estimated that up to 60,000 people are affected by one of these diseases.Rare neurodegenerative diseases can have severe consequences for health, although they are not very common. According to Prof. Anja Schneider, a research group leader at DZNE and Director of the Department of Old Age Psychiatry and Cognitive Disorders at UKB, there is currently no cure for these diseases. It is also not possible to conclusively diagnose the molecular pathology of these diseases during a patient’s lifetime using current methods, as it requires examining brain tissue. For the development of therapies and for stratifying the diseases, diagnostic markers for the underlying pathology are necessary.Stratifying patients based on their disease is crucial for testing targeted and potentially effective disease-modifying treatments,” says Schneider, who is also associated with the University of Bonn. “Our research demonstrates that PSP, behavioral variant of FTD, and most ALS cases can be identified through blood testing, including their underlying pathology. This is the first study to discover pathology-specific biomarkers. Initially, these biomarkers are likely to be used for research and therapy development, but in the future, they could have practical applications.Markers will also play a role in diagnosing medical conditions in the future. However, further research is needed to fully understand their potential. It is especially important to study how these markers develop over time and how early they appear in the course of a disease.”
The new blood test measures tau and TDP-43 proteins, which could be crucial for the diagnosis of certain conditions. This is particularly significant for the “behavioral variant of FTD” that was the focus of this study, as it is the most common type of FTD.There are two different abnormalities in the brain that can cause this, which can only be distinguished by examining tissue after death. In cases where the disease is genetic, DNA analysis can provide certainty during a patient’s lifetime. The blood test now allows for a precise diagnosis to be made while the patient is still alive, even without a mutation. This is essential for testing new therapies against these various FTD pathologies in clinical trials.
Abnormal accumulations
“It is widely known that tau and TDP-43 proteins play crucial roles in FTD, ALS, and PSP, as t rnrnThe abnormal aggregates form in the brain in these diseases. However, the events differ between the diseases. Investigations suggest that the levels of the proteins in the blood reflect these disease processes,” says Schneider. “We have found that the combination of both markers is necessary for the diagnosis of behavioral FTD and its subtypes, while TDP-43 is enough for ALS and the tau protein for PSP. However, for the tau marker, we are specifically looking at two variants, known as isoforms, of the tau protein.”
Tiny bubbles of lipids
The method uses a special twist: The reason for this is that the proteins are not directly measured in the blood plasma. This made the measurements inconclusive, especially because the tau proteins that float freely in the blood are usually fragmented. Instead of measuring the proteins directly, Schneider and his team looked at the levels of two forms of tau proteins and TDP-43 proteins found inside vesicles. These vesicles are tiny bubbles of lipids that are secreted by cells and can enter the bloodstream. Through a multi-stage preparation process, including centrifugation of the blood samples, the researchers were able to capture the proteins contained in the vesicles.Collaborative research The findings are derived from information and blood samples from study groups in Germany and Spain, consisting of a total of 991 adults who were either affected by FTD, ALS, PSP, or were part of a control group of healthy individuals. This setup, which encompassed distinct groups of volunteers, allowed for thorough validation of the results. On one hand, the study involved the DESCRIBE cohorts, where the DZNE, in collaboration with various German university hospitals, collected data and biosamples from individuals with neurodegenerative diseases. This collective included over 700 patients.The “Sant Pau” cohort, managed by the “Hospital de la Santa Creu i Sant Pau” in Barcelona, has joined the project with more than 200 participants from the Spanish side. According to Schneider, in order to include as many study participants as possible and achieve statistically robust results, collaboration across different sites and institutes is necessary for relatively rare diseases. This type of collaboration is a key part of DZNE’s strategy and has been established through structures and procedures over the years. Despite the complexity, the effort pays off and the study serves as a good example of collaboration in medical research, both within Germany and internationally.
