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Sleep behaviour disorder raises Parkinson's disease risk

A Swedish study shows that patients suffering from the rapid eye movement sleep behaviour disorder (RBD) have a risk of developing Parkinson's disease or dementia, because they already suffer from a lack of dopamine in the brain.

Researchers from Aarhus University have discovered that patients with the RBD sleep behaviour disorder lack dopamine and have a form of inflammation of the brain. This means that they are at risk of developing Parkinson's disease or dementia when they grow older.

Do you sleep restlessly and hit out and kick in your sleep? This could be a sign of a disorder associated with diseases of the brain. Researchers from Aarhus University have studied the condition of the dopamine producing nerve cells in the brain and cells that participate in the brain's immune system in people suffering from the rapid eye movement sleep behaviour disorder (RBD).

The study shows that patients suffering from RBD have a risk of developing Parkinson's disease or dementia in the future, because they already suffer from a lack of dopamine in the brain. Parkinson's disease occurs precisely because the group of nerve cells in the brain that produce dopamine stop working.

The RBD sleep disorder is characterised by disturbances in the part of sleep where dreams take place. Healthy people are relaxed and lie still during dream sleep, while people suffering from RBD live out their dreams so that while sleeping they can hit out, kick and shout.

"These patients have an inflammation of the brain in the area where the dopamine-producing nerve cells are found," says one of the researchers behind the study, Morten Gersel Stokholm from Aarhus University and the PET Centre at Aarhus University Hospital.

This is completely new knowledge, as researchers have not previously demonstrated that there is a form of inflammation of the brain in patients who are at risk of developing Parkinson's disease.

"With this study, we have gained new knowledge about the disease processes in the brain in the early initial stages of the disease development. The idea is for this knowledge to be used to determine which patients with the sleep disorder will later develop Parkinson's disease. At the same time, this is also knowledge that can help to develop drugs which can stop or slow the development of the diseases," explains Stokholm about the sleep disorder which most often affects persons aged 50-70, and more frequently men than women.

There are 7,300 Parkinson's disease patients in Denmark. Symptoms are slow movements, often with shaking, together with muscular rigidity. Parkinson's disease is a chronic condition that continues to worsen over time. The disease is somewhat more common in men than in women. Parkinson's disease occurs because the brain lacks dopamine. It is primarily adults who are affected, and the first signs most often appear between the ages of 50-70.

The study is a case-control study. The people behind the project are Stokholm and associate professor, Dr Nicola Pavese in collaboration with medical doctors from the department of neurology and the Sleep Clinic, Aarhus University Hospital and medical doctors from the University Hospital Clinic de Barcelona.

Background: Findings from longitudinal follow-up studies in patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) have shown that most patients will eventually develop the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Neuroinflammation in the form of microglial activation is present in synucleinopathies and is a potential therapeutic target to halt or delay the neurodegenerative process. We aimed to investigate whether neuroinflammation is present in patients with IRBD and its possible relation to nigrostriatal dopamine function.
Methods: In this prospective, case-control, PET study, patients with IRBD and no clinical evidence of parkinsonism and cognitive impairment were recruited from tertiary sleep centres in Spain (Barcelona) and Denmark (Aarhus). We included patients with polysomnography-confirmed IRBD according to established criteria. Healthy controls were recruited through newspaper advertisements. Controls had no motor or cognitive complaints, a normal neurological examination, and a mean group age similar to the IRBD group. In patients with IRBD, we assessed microglial activation in the substantia nigra, putamen, and caudate with 11C-PK11195 PET, and dopaminergic axon terminal function in the putamen and caudate with 18F-DOPA PET. Controls underwent either 11C-PK11195 PET or 18F-DOPA PET. We compared 18F-DOPA uptake and 11C-PK11195 binding potential between groups with an unpaired, two-tailed Student's t test.
Findings: Between March 23, 2015, and Oct 19, 2016, we recruited 20 consecutive patients with IRBD and 19 healthy controls. 11C-PK11195 binding was increased on the left side of the substantia nigra in patients with IRBD compared with controls (Student's t test, mean difference 0·153 [95% CI 0·055 to 0·250], p=0·003), but not on the right side (0·121 [–0·007 to 0·250], p=0·064). 11C-PK11195 binding was not significantly increased in the putamen and caudate of patients with IRBD. 18F-DOPA uptake was reduced in IRBD in the left putamen (–0·0032 [–0·0044 to −0·0021], p<0·0001) and right putamen (–0·0032 [–0·0044 to −0·0020], p<0·0001), but not in the caudate.
Interpretation: In patients with IRBD, increased microglial activation was detected by PET in the substantia nigra along with reduced dopaminergic function in the putamen. Further studies, including more participants than were in this study and longitudinal follow-up, are needed to support our findings and evaluate whether the presence of activated microglia in patients with IRBD represents a marker of short-term conversion to a clinically defined synucleinopathy in the near future.

Morten Gersel Stokholm, Alex Iranzo, Karen Østergaard, Mónica Serradell, Marit Otto, Kristina Bacher Svendsen, Alicia Garrido, Dolores Vilas, Per Borghammer, Joan Santamaria, Arne Møller, Carles Gaig, David J Brooks, Eduardo Tolosa, Nicola Pavese

[link url=""]Aarhus University material[/link]
[link url=""]The Lancet Neurology article summary[/link]

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