Parkinson's disease is known for its characteristic tremor, but this seems to be a bit of an odd symptom. Using brain scans and movement trackers, neurologist and researcher Michiel Dirkx brings the clinical observations under the research lens. This led to a new therapy with a common medication.

‘My grandfather got diagnosed with Parkinson’s disease when I was 12 years old,’ says neurologist and researcher Michiel Dirkx. ‘It was very emotional to see him like that. The movement starts to change, but there are also a lot of other cognitive and behavioural symptoms. That’s very curious.’ Dirkx now researches Parkinson’s disease (PD) at Radboudumc. ‘It wasn’t really a conscious decision because of my grandfather, but I do think the seed was planted back then.’

Dirkx’s work focusses mostly on the tremors – involuntary, rhythmic shaking, which in PD typically starts in a hand or a foot, affecting one side first. ‘Tremor is a bit of an odd symptom,’ explains the researcher. ‘The movements of PD patients become slower and stiffer, but then the tremor is an extra movement – and we don’t really know why.’

‘My grandfather got diagnosed with Parkinson’s disease when I was 12 years old’

For Dirkx, understanding the mechanisms of tremor is about improving the quality of life of his patients. ‘It’s really the things that I see patients struggle with in the clinic that I want to solve and focus on in my research.’ But his scientific curiosity also pushes things further, he explains. ‘When I see an interesting phenomenon in the clinic, I also question why it happens – and in the end, this led to a new therapy for tremor.’

Lewy bodies

Parkinson’s disease is so difficult to tackle due to its progressive nature, meaning that it worsens over time. ‘In the beginning the symptoms are relatively harmless. But every time the patients accept their situation, new symptoms come along,’ explains Dirkx. The patients slowly lose control of their movement, but also of their mind – and there is no therapy that stops or slows it down. ‘It really affects everything in the end.’

In the Parkinson brain, a protein called alpha synuclein begins to fold incorrectly and accumulates in so-called Lewy bodies. These Lewy bodies start in one location of the brain before spreading to other parts, causing the neurons to die. ‘It’s a bit like a virus, but then much slower,’ explains Dirkx. However, the cause of this protein misfolding is not quite clear. ‘We know that only about 20 to 30 per cent is genetically determined and then there are some environmental factors such as pesticides which come into play,’ says the researcher.

‘Every time the patients accept their situation, new symptoms come along’

The spreading of the Lewy bodies explains why the disease is progressive. Neurons in the substantia nigra (Latin for ‘black substance’), a dark brain structure, are the first to degenerate and die. These neurons produce dopamine, a neurotransmitter which acts like a ‘lubricating fluid’ for the brain circuits regulating movement. Dopamine released from the substantia nigra enhances the brain pathways which promote movement and inhibits the signalling which reduces movement. When these neurons are lost – the opposite happens. This is why a deficit in dopamine leads to the specific motor symptoms of PD, slowness and stiffness of movement.

‘Because of that, we give dopaminergic medication, which replaces the dopamine and works pretty well in the beginning.’ However, Dirkx explains further, this doesn’t address the neurodegeneration itself – and as the disease progresses, it becomes much harder to treat the symptoms.

Tremor

Tremor, however, is again a peculiar symptom – it often responds poorly to dopaminergic medication to begin with. Dirkx and his team recorded tremor using hand movement trackers, while also measuring the brain activity of patients. ‘In that way, we know when the tremor starts and the brain regions which are active, leading to tremor,’ he explains. Dirkx’s team found that in the case of patients who don’t respond well to dopaminergic medication, other areas are active, which are not dopaminergic.

Different types of therapies are therefore needed, ‘deep brain stimulation, for example.’ That is a continuous therapy which uses the brain’s innate language – electricity. It involves placing electrodes in specific deep brain regions involved in movement and sending electrical pulses to disrupt abnormal brain signalling caused by the dopamine imbalance.

The overarching goal of Dirkx’s research is to optimize the treatment of tremor. ‘Right now, it usually takes a long time before we figure out which patients have a dopamine-resistant tremor. So ideally, we would know from the beginning, so we can quickly go for deep brain stimulation.’ Using brain scans of patients, they can find the brain regions active during tremor and the connections between them. ‘I aim to create a prediction tool, so the patient doesn’t have to go through all these trial-and-error periods with medication, which can really take a long time.’

Stress

Another window of opportunity for treatment proved to be a curious phenomenon almost every neurologist tests for when seeing a patient – Parkinson tremor is stress sensitive. Dirkx’s team found that this is likely due to the activation of a different area in the brain named locus coeruleus, which produces noradrenaline. Dirkx: ‘Noradrenaline is also the stress neurotransmitter. Once you have to focus on a task, noradrenaline comes into play. You can easily see it, for example, if you stand in the mirror and you perform some mental calculations, then you can see that your pupils dilate.’

‘Propranolol reduces tremor, so this really is an effective therapy’

The brain regions associated with tremor are also sensitive to this noradrenaline, he explains. Once patients experience even subtle stress, such as a social situation, their tremor increases. ‘There is a very common medication known as propranolol, which is mostly given for cardiac patients to lower their blood pressure, but it specifically blocks noradrenaline. We found that if we give it to patients, it reduces tremor, so this really is an effective therapy.’ After the research team recently showed this for the first time, in a large cohort, the guidelines for propranolol were updated. ‘Now many more neurologists prescribe it as an alternative treatment.’