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For Your Patients-REM Sleep Behavior Disorder

REM Disorder Is Highly Predictive of Neurodegenerative Disease, Study Shows

Collins, Thomas R.

doi: 10.1097/01.NT.0000534162.29039.2f
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A prospective cohort study showed that about 6.3 percent of the patients with REM sleep behavior disorder developed Parkinson's disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy each year. By 7.5 years, half of the patients had Parkinson's or DLB. And by 12 years, 73 percent of people had converted to neurodegenerative disease.

LOS ANGELES—Researchers say they now have more proof than ever before that REM sleep behavior disorder is so predictive of the development of Parkinson's disease and dementia that its diagnosis can be used as a practical way to identify patients who are at risk early, and that this predictive value can be used to develop clinical trials for neurodegenerative disease therapies.

The findings, presented at the Contemporary Clinical Issues plenary here at the AAN Annual Meeting in April, are the result of years of observation of patients with the sleep disorder at 24 centers, who compiled their data to get a robust look at the correlations with onset of Parkinson's, dementia with Lewy bodies (DLB), or multiple system atrophy (MSA).

In REM sleep behavior disorder (RBD), the body's normal function of keeping a person in a state of paralysis while dreaming breaks down, allowing people to act out their dreams, sometimes violently, putting themselves and others in danger. The disorder occurs in about 1.0 percent of the population, so it is not particularly rare.

Ronald Postuma, MD, MSc, clinical researcher and movement disorders neurologist at Montreal Neurological Institute and Hospital, said the prospective cohort study showed that about 6.3 percent of the patients developed Parkinson's disease, DLB, or MSA each year. By 7.5 years, half of the patients had Parkinson's or DLB. And by 12 years, 73 percent of people had converted to neurodegenerative disease. The risk remained basically the same throughout that time period.

“It's a relatively straight proportional line throughout — the risk stays constant through time,” Dr. Postuma said. “This is quite striking. The bottom line here is that if you have a patient with polysomnographic-proven REM sleep behavior disorder in front of you, you are probably talking to a patient destined to develop a neurodegenerative disease over the next 10 to 12 years.”



He emphasized the importance that all of the 1,280 patients enrolled in the study had REM sleep behavior disorder confirmed with polysomnography.

Dr. Postuma said Parkinson's and DLB have an unusual prodrome, in that signs and symptoms are very diverse. Most of these symptoms, such as an abnormal sense of smell or constipation, are not that strong, and so can't predict disease by themselves.

RBD is different, he said. “If this is true, if 80 percent of the patients get disease, this has very important implications for the field,” he said. “First of all, it's a chance to do neuroprotective therapy at a time when you could even prevent the disease. And also, if you think about it, if you're a doctor, you never watch a patient get disease. This is a chance to watch people develop a new, neurodegenerative disease out of its prodromal state.”

Perhaps not surprisingly, having an abnormal motor exam on the motor symptoms and motor signs parts of the Unified Parkinson's Disease Rating Scale helped predict development of PD even among the REM sleep behavior disorder patients. Motor scores also predicted development of dementia — strangely, even more strongly than it predicted parkinsonism, Dr. Postuma said.



Cognition was predictive of dementia development, but not parkinsonism, and was the only sub-factor assessed by investigators that didn't have the same correlation for both parkinsonism and dementia, he said.

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Investigators calculated the numbers needed for trials on neuroprotective therapy on a binary outcome basis — whether they protected against parkinsonism and dementia, or not. For a therapy that was only expected to have a fairly robust efficacy, such a trial would only need to have about 300 patients, Dr. Postuma said. With its 1,280 patients, this cohort has enough patients for at least one or two trials, he said.

“I think we now have precise estimates for a clinical trial,” he said. “Personally, I've been doing this for 15 years. I've watched a lot of patients get Parkinson's disease or dementia with Lewy bodies. I guess it's fascinating at first, but it tires on you. We have an opportunity now to really do something about this. The population for a trial is there. It's time to move forward and start preventing disease.”

The study was supported by the Canadian Institute of Health Research.

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Aleksandar Videnovic, MD, MSc, associate professor of neurology at Harvard Medical School, who studies sleep and neurodegeneration, said that although it is not a perfect study, the results offer great promise for vaulting Parkinson's and dementia research forward.

“The very important outcomes of this study are estimates of the sample size needed for a future disease-modifying trial in the RBD population,” he said. “We need over 300 patients for a two-year trial with a relatively robust effect size of 50 percent.”

The trial had limitations, however, he said. The centers lacked a standardized protocol, and there were differences in the depth of the assessments of the patients, in follow-up schedules, and in the methods used to ascertain neurodegeneration predictors. This, he said, “makes interpretation of some study findings a bit challenging.”

He added: “This study doesn't really allow for a distinction between study biomarkers of neurodegeneration versus dynamic markers that may be sensitive to a change reflective of a neurodegenerative process.”

Still, Dr. Videnovic said, the study “positions RBD as a very important target for future trials directed at disease modification.”

Trial development nonetheless poses challenges, he said. There will be a need for recruitment of large numbers of patients, “given the likely scenario of having neuroprotective agents to test in the near future.” The inclusion and exclusion criteria will be critical as well, and the endpoints will need to be carefully chosen so that they can capture conversion to disease and test the effects of interventions “within the context of a reasonable trial duration” and within regulatory rules.

The findings also raise questions about how clinicians should talk to patients about the implications for further illness when they are found to have REM sleep behavior disorder.

“We certainly face a challenge in what to say to our patients with that behavioral disorder,” he said. “As the knowledge about the RBD and its associations with neurodegeneration accumulates, it is critical that we develop a strategy on how to best incorporate these relevant findings into everyday clinical practice.”

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Dr. Postuma has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biotie, Roche/Prothena, Teva Neurosciences, Jazz Pharmaceuticals, Novartis Canada, Theranexus, and GE HealthCare.

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•. AAN Annual Meeting Abstract CCI.003: Postuma R, Iranzo M, Manni R, et al. Predictors of neurodegeneration in idiopathic REM sleep behavior disorder: A multicenter cohort study
    © 2018 American Academy of Neurology