Looking for the invisible protein behind Parkinson's disease

Professor Bert Windhorst is developing a PET tracer that enables Parkinson's disease to be detected at an earlier stage. This will allow new treatments to be evaluated more effectively. It brings earlier diagnosis and more effective medicines one step closer.

“If you cannot see what is happening in the brain, you do not really know whether a treatment is actually working.” With that thought in mind, Professor Bert Windhorst is working on one of the biggest challenges in Parkinson's research: developing a PET tracer that makes the protein α-synuclein visible. If successful, doctors will be able to diagnose the disease earlier and determine more quickly whether medicines are actually affecting the disease process.

This is urgently needed. It is particularly difficult to directly investigate what is happening inside the brain. Yet this knowledge is essential for detecting diseases such as Parkinson's disease and Alzheimer's disease at an earlier stage and for developing new treatments.

This has been the focus of Bert Windhorst, Professor of Radiopharmaceutical Chemistry and Head of the Tracer Center Amsterdam, throughout his career. He develops PET tracers: radioactive compounds that make disease processes visible at the molecular level.

Looking where you normally cannot look

That Bert Windhorst would one day develop PET tracers was never a childhood dream. After studying radiopharmaceutical chemistry, he found his way into the world of radiopharmaceuticals by chance. “I more or less stumbled into it,” he says with a smile. “But I found it so interesting that I stayed.”

What still appeals to him after many years in the field is how closely his work is connected to patients. “In fact, you are developing a diagnostic medicine that is used directly in people. What you develop can almost immediately be applied in the clinic. That makes it very tangible.”

A PET tracer is a radioactive compound that is injected in a very low dose. The tracer binds to a specific molecule involved in a disease process. This allows researchers to see where a disease process is taking place, how active it is and to measure whether a new medicine has an effect on it.

From MS and Alzheimer's disease to Parkinson's disease

“In principle, PET can be used to visualise almost any disease. This is particularly valuable in brain diseases. You cannot simply remove a piece of brain tissue to investigate what is happening. That is why imaging techniques such as PET are so important.”

During his career, Bert Windhorst has contributed to the development of several dozen PET tracers. One of these successes is a tracer for neuroinflammation, which is now used in research into multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease.

His current challenge is to develop a good PET tracer that can detect Parkinson's disease at a much earlier stage. “At present, these protein accumulations can only be confirmed with certainty after a patient has died.”

Intervening at an early stage

Parkinson's disease is characterised by accumulations of the protein α-synuclein. “If you can eventually remove these accumulations with a medicine that still has to be developed, you are essentially addressing the cause of the disease. But first you need to be able to reliably demonstrate where that protein is located. And for that we need a good PET tracer. Only then can you objectively determine whether a new medicine actually reduces the protein accumulations.”

This is also what makes the development of new medicines so complicated. In diseases such as Parkinson's disease and Alzheimer's disease, irreversible damage has often already occurred before patients present with symptoms. As a result, new medicines are often introduced only after a large proportion of brain cells has already been lost. “You cannot repair damage. You can only try to prevent further damage. That means you have to intervene much earlier.”

In Alzheimer's disease, PET has already demonstrated how valuable a tracer can be. Thanks to a PET tracer for beta-amyloid, researchers can measure whether new medicines actually influence the disease process. “These medicines are not yet ideal. But without such a tracer, we would never have been able to take that step.”

Why different research methods are needed

The biggest challenge is that researchers cannot yet demonstrate whether a new PET tracer actually binds to α-synuclein. The complex protein accumulations that develop in the human brain cannot yet be adequately reproduced using cell models or computer models. “What we create in the laboratory does not sufficiently resemble what happens in the human brain. Most likely, it is precisely the conditions inside the brain that determine how proteins aggregate. We cannot replicate those conditions properly.”

He continues: “We want to limit the use of animal models as much as possible, but in this case we have no other choice. Otherwise we cannot move forward with this important research, which may ultimately provide solutions for diseases such as Alzheimer's disease and Parkinson's disease.”

That is why a Parkinson's disease model in macaques is being developed at the BPRC. It forms the essential link between laboratory research and research in patients. This enables researchers to determine whether promising PET tracers actually do what they were designed to do. “Only when there is convincing evidence can they be responsibly tested in people.”

Bert Windhorst does not see NAMs (animal-free methods) and animal models as competing approaches, but as consecutive steps within the same research process. “You can do a great deal of research using animal-free models. But sometimes you need an animal model to collect sufficient evidence before you can responsibly begin research in patients. It is not a matter of either-or, but of using the right research method at the right time.”

The real breakthrough

The same applies to the three PET tracers his research group is currently developing. “We believe they are good. But without convincing evidence, we cannot responsibly move to studies in patients, nor will we obtain funding for that next step. An animal model using macaques can provide that evidence.”

He expects it will take at least another ten years before a PET tracer for α-synuclein is actually used in clinical practice.

But for him, the real breakthrough begins much earlier. “For me, the greatest scientific breakthrough will be the moment we can demonstrate in patients that our tracer really does what it was designed to do,” he says. “Only then will we know for certain that we are visualising the right disease process.”

‘Every step provides another piece of the puzzle’

From that moment on, researchers will be able to assess much more quickly which medicines actually influence the disease process. This increases the likelihood that, in the future, patients can be treated before irreversible brain damage occurs.

According to Bert Windhorst, medical progress does not result from a single research method, but from different research methods complementing one another. “Every step provides another piece of the puzzle. Only by putting those pieces together can you ultimately translate new insights into better diagnostics and better treatments for people with Parkinson's disease and other brain disorders.”