Still unknown what triggers Parkinson's disease

"I have several patients who were born in the 1970s. In the Stockholm area, there are about 50 patients diagnosed with Parkinson's before the age of 40," says Per Svenningsson, Professor of Neurology at Karolinska Institutet's Department of Clinical Neuroscience and the Department of Neurology, Karolinska University Hospital in Huddinge.

What causes or triggers Parkinson's disease is still unknown. For a very long time, until into the 1990s, the prevailing view was that there were no genetic causes of the disease. At that time, the focus was entirely on environmental factors such as pesticides and various heavy metals. For example, water from private wells containing high levels of heavy metals is considered to increase the risk of being affected.

"People who live in the country have a slightly higher incidence of Parkinson's than those who live in cities," says Per Svenningsson.

But in recent years, knowledge about the genetic links to Parkinson's has increased greatly, and this has set old truths on their heads. We now know that a smaller proportion of all Parkinson's cases is entirely caused by hereditary factors and that there are many risk genes (see separate article).

Interplay of heredity and environment

For the vast majority of cases, it is today believed that the cause is an interplay between the genetic risk genes and environmental load. Just as there are environmental factors that increase the risk, there are factors that appear to provide protection against the disease. But for Parkinson's disease, it is not the usual lifestyle factors of more vegetables and exercise that gives protection. It could be said to be almost the reverse.

"Epidemiological studies have revealed three factors that reduce the risk of Parkinson's. These are nicotine, caffeine and high urate values," says Per Svenningsson.

"This means that it often feels unfair when someone is affected by Parkinson's where the person is frequently a clean-living person who neither smokes nor drinks a lot of coffee nor eats juicy, rare steaks," he says.

When a patient is diagnosed with Parkinson's, he or she has already had the disease for many years, perhaps as long as 5-10 years.

"When the symptoms begin to show, the patients have already lost more than 50 per cent of their dopamine-producing cells in the brain," says Per Svenningsson.

In recent years, new research has shown that there are much earlier symptoms of the disease. Such things as a reduced sense of smell, constipation, depression or a sleep disorder that involves not lying still in dream sleep, but moving vigorously, are now being linked with Parkinson's disease.

"It may be that people are looking for these symptoms, and then they know that they have an increased risk of developing Parkinson's. In our research, we now follow such patients in order to ascertain how great that risk is," says Per Svenningsson.

One idea would of course be to use these early symptoms to discover the patients earlier, but besides the symptoms being a little too common to work well as markers for the disease, there is another concern.

"We do not have a disease-modifying drug. The major breakthrough would be to find a disease-modifying drug, like for MS," says Per Svenningsson.

Dopamine-producing brain cells

What causes Parkinson's typical motor symptoms, which eventually lead to the diagnosis, is that the dopamine-producing brain cells are broken down and destroyed. The symptoms are due to a lack of dopamine in the brain and this is also the reason why substances that stimulate the dopamine system work.

But the dopamine-stimulating treatment only relieves symptoms, it does not affect disease progression and, in time, the remaining dopamine-producing cells also die. This is why the effect of the treatment gradually diminishes and may need to be supplemented with additional therapies.

Relatively recently, researchers have also been able to demonstrate that it is not only the dopamine-producing cells that are destroyed by the disease, but also other signalling systems in the brain are affected, resulting in reduced levels of neurotransmitters such as acetylcholine, serotonin and norepinephrine. This results in non-motor symptoms such as a fall in blood pressure after getting up, disturbed sleep, worry/anxiety, depression and dementia problems.

"Parkinson's disease is classified as a motor disorder, but many patients themselves experience that they have more problems with the other symptoms. This is something that has drawn more attention in recent years," says Per Svenningsson.

Clearly undertreated

Previously, these symptoms were clearly undertreated, and there is still a risk that the healthcare system misses them. This is something Per Svenningsson thinks is a shame because they can often be treated with relative success.

"As a doctor, you have to actively ask about them because patients do not always volunteer this information. They do not always make the connection to depression and memory failure," he says.

Ever since Arvid Carlsson's discovery in the late 1950s, L-DOPA, or levodopa, has been the first choice for treating dopamine deficiency in Parkinson's disease.

It is the treatment that has the best effect, but this effect lasts for quite a short time, and the medication needs to be taken frequently, three to four times a day. Even so, wearing off can occur, where the disease breaks through. For this reason, levodopa treatment is often combined with drugs that slow the breakdown of dopamine in the brain in order to prolong the effect. Alternatively, levodopa can be administered on a more continuous basis through surgically implanted tubes directly into the duodenum using what is known as a Duodopa pump, a technique that was developed in Uppsala in the 1990s.

There are also drugs that affect the dopamine receptors in a similar way to dopamine, but with a longer active effect. These agents can be an alternative to levodopa, especially in a little younger patients.

A somewhat strange side effect of these drugs, affecting between one in seven and one in ten patients, is what doctors call impulse control disorder. This is because dopamine is not only involved in motor control, but also plays an important role in the human reward system. So drug treatment may, in some individuals, result in an excessive behaviour that might among other things lead to eating disorders, addictive gambling or hypersexuality.

Devastating consequences

"It can have devastating consequences. It might lead to the patient gambling away a lot of money, getting a strange collecting behaviour, becoming hypersexual or the like," says Per Svenningsson.

The only solution to an impulse control disorder is to change treatment. As the disease progresses, patients become increasingly worse, the effect of medication diminishes and more troublesome side effects arise. Sometimes these side effects can be suppressed by older drugs such as anticholinergics and amantadine, which may on the other hand have other troublesome side effects.

For severe cases where the patient is still under the age of 70, there is sometimes the opportunity for DBS or Deep Brain Stimulation. This means that doctors implant an electrode in the brain driven by a pacemaker that electrically stimulates the brain and suppresses tremor and rigidity.

Worldwide, about 100,000 patients have undergone surgery. In Sweden, approximately 300 patients have received this treatment and, according to Per Svenningsson, this is probably too few.

"The treatment is more effective than the best medicine and you can cut down significantly on medication after surgery," he says.

The procedure is relatively spectacular because the patient is mostly awake when brain surgeons implant the electrode. The brain has no pain cells, so it does not need any anaesthetic. This helps the surgeon to find the right place.

"The area to be stimulated is about the size of a grain of rice. That's why it's important for the patient to be awake so that you know the right place is being stimulated. When the patient stops shaking, you know you've come to the right spot," says Per Svenningsson.