Do viruses play a role in Parkinson's disease?

Parkinson's disease is the fastest-growing neurological disorder in the world. Yet we still do not know exactly how the disease develops. Increasingly, researchers are pointing to viruses as a possible factor. At the BPRC, scientists are investigating whether infections, such as COVID-19, may play a role. “If we better understand what happens in the brain after an infection, we may be able to intervene earlier, before people actually become ill,” says neuroscientist Jinte Middeldorp.

“We have known for some time that viral infections, such as influenza, can be a risk factor,” says Jinte Middeldorp, Head of the Department of Neurobiology and Ageing at the BPRC. “After the Spanish flu pandemic in 1918, for example, doctors observed that more people subsequently developed parkinsonism.” This is a collective term for neurological disorders that resemble Parkinson's disease.

Similar indications are emerging today. Large population studies are investigating whether more people develop conditions such as Parkinson's disease or Alzheimer's disease following the COVID-19 pandemic. However, these studies mainly show the end result. What happens in the brain much earlier in the disease process often remains invisible or out of view. “The first symptoms of Parkinson's and Alzheimer's actually begin around fifteen years before people visit a doctor with complaints.”

What do researchers see in the brain after an infection?

And that is precisely where the strength of the BPRC's research lies, according to Jinte. In the study, which received funding from ParkinsonNL, brains from monkeys that had experienced a SARS-CoV-2 infection from our brain bank are compared with those of healthy animals that had not been infected. Because these animals live under controlled conditions and are monitored extensively, researchers can see very precisely what changes occur. “In humans, it is virtually impossible to follow this process with such precision.”

In a specific brain region, the substantia nigra, researchers are seeing something remarkable. This is where the dopamine-producing cells that are lost in Parkinson's disease are located. Following a SARS-CoV-2 infection, we see a significantly lower number of these cells compared with the brains of control animals. “The effect is not as pronounced as in Parkinson's disease, but we can clearly measure it,” says Jinte.

Researchers also observe inflammatory responses in the brain, including changes in immune cells known as glial cells. These cells normally provide protection, but when activated for prolonged periods, they can also cause damage.

These are signs that the immune system is active in the brain, something that also plays a role in Parkinson's disease and Alzheimer's disease. The animals themselves do not develop Parkinson's disease, she explains. “But what they show may represent an early step in the disease process.”

These findings are consistent with other research. For example, studies conducted by Amsterdam UMC using brain tissue from people who died from COVID-19 have revealed similar changes, including the loss of dopamine-producing cells. Laboratory studies using nerve cells grown in culture dishes have also shown that this type of neuron is particularly vulnerable to the virus.

Damage that does not stop immediately

What makes the BPRC study unique is that researchers are not looking at a single moment in time, but are following the process over time. They examine changes 7 and 22 weeks after infection and now also up to 12 months afterwards.

Researchers analyse cerebrospinal fluid collected before and after infection. In this fluid, they observe a protein that is released when nerve cells are damaged. Levels of this protein remain elevated even months after the infection. This suggests that the process does not stop immediately.

“Even twelve months later, we still see signs of damage to nerve cells,” says Jinte. This raises important research questions. Does the damage worsen over time, or does it stabilise? And what does this mean for people who have experienced an infection?

Early signs of a disease that only becomes visible later

Parkinson's disease does not appear suddenly, Jinte continues. The disease develops gradually and often begins ten to fifteen years before the first symptoms become visible. This makes it difficult to identify causes. By the time someone visits a doctor, the process has already been underway for many years. This research aims to make that early phase visible.

“We think infections may act as a kind of trigger,” says Jinte. “Not as the sole cause, but as something that sets the process in motion, and some people may be more susceptible to this than others.”

This may also explain why not everyone who experiences a viral infection becomes ill. It is likely a combination of factors.

The major questions for the coming years

The research is still in its early stages, but the direction is clear. Researchers want to better understand the role of infections and how this interacts with other factors. These include multiple infections over time, combinations of different viruses and ageing. They are also investigating whether vaccination may have a protective effect.

In addition, researchers are taking a broader look at how Parkinson's disease develops. They are studying not just one brain region, but multiple regions involved in the disease. Using techniques such as RNA sequencing, they aim to identify the biological processes that play a role.

There are also indications that the disease does not always begin in the brain, the neuroscientist explains. In some cases, the process appears to start in the gut, possibly influenced by the microbiome. Furthermore, intestinal diseases have been associated with an increased risk of Parkinson's disease.

Loss of smell, a well-known early symptom, also points to the involvement of brain regions that are in direct contact with the outside world. Whatever the route may be, the goal remains the same: to understand earlier what is happening. According to Jinte, that is where the key lies. “If you know earlier who is at risk, you may also be able to intervene earlier. And ultimately, that is what we are working towards.”