What do REM sleep disturbances have to do with Parkinson’s disease?
Bente Olsen in Zleep Hotel. Advanced measuring equipment monitors Bente and her sleep.
Scientists at Aarhus University Hospital are conducting research into REM sleep disorders in order to learn more about the main mechanisms underlying Parkinson’s disease. In the long term, they hope their observations will help to slow down the development of Parkinson’s in some patients before it really gathers momentum.
One morning not so long ago, Bente Olsen woke up in a room in Zleep Hotel in the north of Aarhus with a myriad of thin electrodes leading from her head, arms and legs to a range of measuring devices. From the top of a tripod, a video camera also kept a careful eye on her every move. It was quite the morning, and more was to come.
No sooner was Bente free of all the electrodes than she was due in a proper laboratory in a neighbouring building where scientists from Aarhus University Hospital, the ones who had set up all the equipment in the hotel room, were standing by to conduct another battery of tests.
All because she suddenly felt tremors in one leg in summer 2021.‘That's how it began,’ recalls Bente Olsen, an alias designed to protect the privacy of the subject, who did not wish to be named.
Bente is in her mid-60s, a manager in the public sector, married, has grown-up children, enjoys an active life – and had never had tremors like the ones that afflicted her last summer.
She went to her doctor, who referred her for various examinations, including one with a neurologist to ascertain whether or not she had a brain tumour. Thankfully, she didn’t, but it emerged that she has Parkinson’s disease, a neurodegenerative disorder known to cause tremors.
It was this diagnosis that led to her spending the night in Zleep Hotel hooked up to all that equipment. Bente had agreed to a polysomnography (PSG) test, which records the sleeping subject’s brainwave activity, eye movements and muscle activity and then analyses the data afterwards. To complete the information-gathering process, an infrared camera follows the subject and detects in the dark whether — and, if so, how — they move around in bed or are physically active in other ways while asleep.
One reason the doctors at Aarhus University Hospital rent hotel rooms to house all of the equipment and run PSG tests is that it feels a bit more like home, a little less institutional than an actual laboratory. ‘But I actually slept really well despite all the equipment,’ Bente said the next morning.
PSG tests are an important part of medical science’s attempts to gain a better understanding of Parkinson’s, including where in the body the disease originates, a question on which scientists around the world have concentrated more and more in recent years. Some researchers, including Professor Per Borghammer from the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital, are considering a hypothesis based on clinical findings that we might describe in everyday language as ‘bottom-up’ or ‘top-down’ scenarios.
When Parkinson’s starts in the gut, it usually does so years before the disease is actually diagnosed, often 10–15 years earlier.
We now know that in a very high number of cases, we must assume that certain dream-sleep (REM) disorders are indicators of Parkinson’s in the intestinal system.
‘This hypothesis assumes that Parkinson’s either begins in the gut and spreads from there via nerve pathways up to the brain or begins in the brain and spreads down through the body,’ the professor explains.
‘When Parkinson’s starts in the gut, it usually does so years before the disease is actually diagnosed, often 10–15 years earlier. We now know that in a very high number of cases, we must assume that certain dream-sleep (REM) disorders are indicators of Parkinson’s in the intestinal system. Statistically, if you suffer from sleep disturbances like these, you are at a significantly higher risk of developing Parkinson’s.’
And that is why Parkinson’s researchers use polysomnography (PSG). ‘PSG lets us identify these specific REM-sleep disorders,’ explains Borghammer, who was awarded a DKK 30 million Lundbeck Foundation Professorship in 2021 for his Parkinson’s research.
SEPARATE BEDROOMS
When Danish doctors talk about these sleep problems, they use the international term “REM Sleep Behaviour Disorder” and the abbreviation RBD.
‘RBD is both a dramatic and in many ways mysterious state,’ explains Tatyana Fedorova, a doctor, PhD Fellow and part of Professor Borghammer’s team, who spends part of her research time running sleep tests like the one on Bente Olsen. In fact, it was Fedorova who attached the numerous electrodes to Bente’s head.
Tatyana Fedorova was awarded the Lundbeck Foundation Talent Prize in 2021. She conducts research into the REM sleep disorder RBD and how Parkinson’s disease develops.
‘One of the most striking aspects of RBD is that the individual afflicted by the disorder is often completely unaware that something is wrong,’ she explains. ‘The same can’t be said of their partner or spouse with whom they share a bed. They’re rarely in any doubt because RBD, which in 70–80% of all diagnosed cases affects men, is a very unusual disorder.
The characteristic feature is that sufferers physically act out their dreams. In some cases, they’ve been known to attack their spouse in the middle of the night while both are asleep. Afterwards, when they hear about it — and are possibly asked to see a doctor — they won’t have the remotest recollection of the episode.
That’s why we also put electrodes on the person’s arms and legs when we do a PSG test because it lets us detect movements. The video recording with the infrared camera lets us document the nature of the physical activity.’
‘In other cases, the sleeping person will dream, for example, that they’re being chased and literally try to escape, often ending up falling out of bed and, in the worst-case scenario, breaking something or other,’ Fedorova continues. ‘Often their nose as their face hits the floor. That’s not unusual. Nor is it unusual for spouses to decide to sleep in separate bedrooms at some point. I've heard that story more than once from our patients.’
Although science is still having trouble working out exactly what REM sleep disturbances have to do with the development of Parkinson’s, evidence suggests that small centres in the brainstem play a role, including an area called the subcoeruleus.
‘These centres are involved in a state characteristic of normal REM sleep. For example, REM sleepers may experience all sorts in their dreams but will lie still throughout. And they won’t exhibit muscle tension — or tonus. This is quite the opposite of the state that characterises RBD, in which the dream is physically enacted. The assumption is that the sleep centres may be affected by the misfolding of certain proteins in the brain, something that happens with Parkinson’s disease, so that the centres can no longer cope with their task of keeping the body fully at rest during the REM sleep phase,’ Fedorova says.
More to read:
Tatyana Fedorova, doctor and PhD student, is receiving a 2021 Lundbeck Foundation Talent Prize for her research on Parkinson's disease.
SEVERELY UNDERDIAGNOSED
The American psychiatrist Carlos Schenk was the head of a research group that caused a major stir in 1986 when it published its findings for the first time in an article in Sleep, the world’s highest-ranking scientific journal on the subject. As this was the first time the phenomenon had been studied in detail, it had not previously been recognised as a separate disorder. It was also Schenk who subsequently suggested some kind of potential correlation between RBD and Parkinson’s.
Since then, researchers in many countries have investigated numerous aspects of possible links between RDB and Parkinson’s, as well as some other neurodegenerative disorders that lead to misfolding of the same proteins in the brain, including Lewy Body Dementia.
There is broad scientific consensus that, statistically speaking, RBD is an ominous harbinger of things to come. Over the next 10–15 years, up to 90% of people diagnosed with it will develop either Parkinson’s or Lewy body dementia. To date, there is no treatment to stop these diseases, but Professor Borghammer points out that RBD, which is estimated to affect about a third of all Parkinson’s patients and two-thirds of all Lewy Body Dementia patients, also provides certain opportunities.
For instance, there are usually many years between discovery of the sleep disorder and diagnosis of Parkinson’s disease. The patient can make use of this right away – as soon as the sleep disorder is identified – by embarking on a programme of physical training. Scientific studies have shown that exercise can reduce the rate at which Parkinson’s progresses, typically by three to five years.
‘It’s also important that researchers and healthcare professionals become better at identifying patients with RBD. Because as soon as we find a medical treatment that will slow the progression of Parkinson’s, we need to start treating patients at as early a stage of the disease as possible. The sooner we get started, the better,’ the professor explains.
Borghammer also points out another reason why early detection of RBD is important. ‘Because sleep medication can actually help alleviate the sleep disturbances caused by RBD. That alone can have huge significance for the patient, not to mention their partner or spouse – although it unfortunately doesn’t stop Parkinson’s or Lewy Body Dementia from developing.’
HOME TESTING
Early detection is, however, still a problem. Professor Borghammer explains that specialists in Parkinson’s and other dementia disorders are aware that sleep clinics can test for behaviour that might indicate RBD, but this information has not been conveyed effectively enough to the nation’s GPs.
‘This is one reason why RBD is severely underdiagnosed. Given the size of the population and the fact RBD is mainly observed in the over 60s, we know that many thousands of Danes have it. But no more than 1,000 have been diagnosed. The vast majority of the others don’t know they have it.’
However, it isn’t enough “just” to refer many more people for a PSG test like the one Bente Olsen had. PSG takes a lot of time, equipment and staff. In an attempt to solve this problem, the research team has spent the last couple of years working with a team of engineers at Aarhus University, who have now developed a mobile version of the equipment.
‘It’s the size of a smartphone and only uses a few electrodes on the head and body, and we’ve just started testing it. The idea is that patients suspected of having RBD will borrow the device and use it at home instead of coming into the clinic for a traditional PSG test. If that turns out to be realistic – so, if the mobile version proves to be as accurate as we think it will – then we’ll be able to test far more people for RBD,’ explains Fedorova, the recipient of a Lundbeck Foundation Talent Prize in 2021 for her Parkinson’s research.
To ascertain how well the mobile device works, the doctors at Aarhus University Hospital are fitting the small mobile device and the standard equipment to patients when they spend the night in Zleep Hotel for a PSG test, she explains.
‘It lets us compare results, but we haven’t finished analysing them yet.’
A MEDICIAL ‘VACUUM CLEANER’?
In summer 2021, the drug Aducanumab was approved for the treatment of Alzheimer’s disease in the United States, but the company behind it has not yet received the equivalent authorisation to market the drug in the EU, where authorities have asked for more information.
Aducanumab is intended for use in the early stages of the disease. It doesn’t cure Alzheimer’s, which is another neurodegenerative disorder, nor stop it from ravaging the brain. What it can do to a limited extent is “vacuum” the protein accumulations caused by Alzheimer’s and, it is claimed, slow the progression of the disease.
This claim has attracted the attention of many Parkinson’s researchers, and they are beginning to speculate:
What if we could produce something similar to Aducanumab? What if we could design a drug that removes, or “vacuums”, the protein accumulations seen in Parkinson’s disease and Lewy Body Dementia with an efficacy of 10%, as reported for Aducanumab?
If that were the case, it would make sense to conduct routine tests for REM sleep disorders in people in their 50s. In theory at least, PSG tests would identify up to 50% of all those in the process of developing either Parkinson’s or Lewy Body Dementia and do so a good 10-15 years before the symptoms become serious.
‘And at that early stage, even a drug with limited efficacy would probably make a significant difference because, by that point in the process, not so much of the misfolded protein that characterises the two diseases has formed,’ Professor Borghammer explains.
Fedorova says that the idea of using medicine to slow down the accumulation of misfolded protein is also one of the topics that will be debated at “Grand Challenges in Parkinson's Disease” this year, an international Parkinson’s congress in the United States.
‘However, misfolded protein could perhaps be interpreted differently. It could, for instance, “merely” be a symptom of existing, underlying problems linked to the nervous system – and whether this is the case will also be debated.
Finally, there are currently a number of studies being conducted in the Parkinson’s research community on “drug repositioning”. In other words, attempts are being made to find out whether medicines approved for completely different purposes could, in reality, also be used for neurodegenerative disorders such as Parkinson’s.’
Bente Olsen, who spent the night with electrodes on her head, arms and legs in a hotel room in the north of Aarhus, is one of the newly diagnosed Parkinson’s patients Tatyana Fedorova has tested for REM Sleep Behaviour Disorder (RBD) as part of her research project.
‘I haven’t received the results of the test yet,’ says Bente, ‘but I don't think I have RBD because there’s no difference between my sleep in the past and now. I’ve never had the kind of problems described for RBD. And my husband, who I married aeons ago, has never said he feels threatened by me while I’m sleeping,’ Bente explains.
As part of Fedorova’s research project, Bente will be offered a new sleep test again in three years. But by then, she might be able to skip the trip to Zleep Hotel and do it in her own bedroom as the doctors at Aarhus University Hospital are currently testing the quality of the new mobile device.
Parkinson’s disease has been known to medical science for about 200 years.
Ultimately, it causes the patient’s brain to break down due to a harmful accumulation of the protein alpha-synuclein in the nerve cells.
The hypothesis that Parkinson’s can either begin in the gut and spread from there via nerve pathways up to the brain or begin in the brain and spread down through the body has been the subject of a series of scientific studies over the last two decades.
Professor Per Borghammer from the Department of Nuclear Medicine & PET-Centre at Aarhus University Hospital is one of the scientists conducting research in this field. In 2018, he spearheaded a project involving colleagues from the University of Southern Denmark and universities in Germany and the UK. The results of its work, which was partially funded by the Lundbeck Foundation, were published in the research journal Lancet Neurology.
The team studied 22 Danes aged 50–85, all of whom had been diagnosed with RBD. In approximately 90% of cases, RBD is an indicator that the subject will contract Parkinson’s or Lewy Body Dementia at some point in the next 10–15 years.
The 22 subjects, none of whom had been diagnosed with Parkinson’s, were first examined for symptoms of the disease, including tremors and slow movements. None were observed.
They were then examined using five different advanced scanning techniques to map out any nerve damage inside and outside the brain. And this was when the surprising find was made.
‘Most of the participants had fully developed damage to the nervous system in the gut and heart, just like patients diagnosed with Parkinson’s. On the other hand, the dopamine systems in their brains were intact,’ Professor Borghammer explains, ‘and this reinforces the suspicion that Parkinson’s may begin in the peripheral nervous system – that is, outside the brain – many years before the diagnosis itself is made.’
‘There are several reasons to assume that it happens in the gut,’ the professor continues, ‘including that Parkinson’s patients often report suffering constipation for years before they are diagnosed with the disease.’
A later study of newly diagnosed Parkinson’s patients by Professor Borghammer’s team at Aarhus University Hospital underpins the results of the 2018 study. The findings concluded that patients with a serious sleep disorder in the form of RBD also had peripheral nerve damage — i.e. nerve damage outside the brain while the nerve damage in those patients who did not have RBD was often exclusively in the central nervous system — i.e. in the brain.