People with Rapid Eye Movement (REM) sleep behavior disorder are living out their dreams. For example, while sleeping safely in bed, they can raise their arms to catch an imaginary ball or try to run away from an illusory attacker. Such actions are more than just a nuisance. People with this disorder have a 50 to 80 percent chance of developing severe neurodegenerative disease within a decade of being diagnosed.
An international team led by researchers from The Neuro (Montreal Neurological Institute-Hospital) at McGill University, Washington University School of Medicine in St. Louis, and the Mayo Clinic in Rochester, Minnesota, has a five-year fellowship expected to be worth 35 , $ 1 million will be given to develop biomarkers that show which people with the sleep disorder will develop neurodegenerative diseases, what specific diseases will develop, when symptoms will appear, and how quickly the diseases will progress. This grant -; from the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS), both US National Institutes of Health (NIH) -; will help lay the foundation for clinical trials aimed at preventing the progression of the troublesome disease into a debilitating disease.
REM sleep behavior disorder is linked to Parkinson’s disease, a state of movement; Dementia with Lewy bodies that causes cognitive decline; and multiple system atrophy, in which the ability to regulate involuntary functions such as blood pressure, breathing, and bladder and bowel function deteriorates.
The primary goal of this research is to find ways to reliably identify early Parkinson’s disease, Lewy body dementia, and multiple system atrophy. When we do, we can start planning disease prevention studies. So far we have very good clinical predictors of disease, but biomarker research is still catching up. Biomarkers are important in determining exactly what stage of the disease people are in so that more targeted therapies can be offered. “
Dr. Ronald Postuma, Co-Principal Investigator, The Neuro and the Research Institute, McGill University Health Center
“The likelihood of people with REM sleep behavior disorder developing neurodegenerative disease is quite alarming, and there are currently no treatments to reduce that risk,” said Dr. Yo-El Ju, neurologist and co-director of studies at Washington University. “We have no way of predicting whether and how quickly someone will get one of these diseases or which ones. And we certainly do not know how we can prevent it.”
Usually people are paralyzed in REM sleep, the phase of sleep in which dreaming takes place. Acting out dreams is an early sign that something in the brain is not working as it should. REM sleep behavior disorder is linked to diseases caused by the accumulation of abnormal clumps of the protein alpha-synuclein in the brain. Such lumps often condense early in the course of the disease in a part of the brain that paralyzes the body during REM sleep. When this area becomes damaged, people start beating around while dreaming.
Several drugs and immunotherapies targeting alpha-synuclein are currently being developed and may be available for clinical trials in REM sleep behavior disorders. But first, scientists need to identify a series of results on specific tests or biomarkers for impending neurological disease in people with REM sleep behavior disorder.
“Information predicting the timing and type of synucleinopathy disorder is almost certainly hidden in one or more of the biomarkers being evaluated in this study,” said Dr. Bradley Boeve, a Mayo Clinic neurologist and co-lead researcher on the fellowship. “If we can identify biomarkers that predict the future, we can focus on those biomarkers for upcoming clinical trials aimed at delaying the onset or preventing dementia or parkinsonism.”
The NAPS consortium
Dr. Boeve, The Little Family Foundation Professor of Lewy Body Dementia at the Mayo Clinic, and Dr. Ju, Barbara Burton and Reuben Morriss III Professor of Neurology at Washington University founded the North American Prodromal Synucleinopathic (NAPS) Consortium in 2018 to bring together a group of people with REM sleep behavior disorder and develop standardized tools to study them. Over 350 people with REM sleep behavior disorder have enrolled in the NAPS consortium. The new grant funds a larger study aimed at identifying biomarkers in these individuals as well as new participants.
This larger study, called NAPS2, is being led by Drs. Ju, Boeve and Postuma. This study will follow approximately 430 participants with REM sleep behavior disorder and 60 people without sleep problems for five years. Patients and control subjects are regularly subjected to extensive clinical examinations and overnight sleep studies. They will also provide blood samples and, if requested, cerebrospinal fluid. Participants with REM sleep behavior disorder will also have brain scans.
“NAPS2 is another example of the coordinated and collaborative support NIH provides to advance the discovery and understanding of devastating brain diseases,” said Mack Mackiewicz, PhD, program director in the NIA Division of Neuroscience and NIA project scientist on the fellowship . “This project, which looks at sleep as a risk factor for dementia, is just one example of the broad spectrum of research the NIH is promoting on neurodegenerative diseases.” NIA and NINDS fund NAPS2 equally with joint scientific contributions and NIA oversees the project.
About Lewy Body Diseases
More than two million people in the United States are living with Lewy Body Disorder, a group of diseases caused by alpha-synuclein clots in their brain. These so-called synucleinopathies include dementia with Lewy bodies, Parkinson’s disease and multiple system atrophy. Taken together, they are the second most common neurodegenerative disease after Alzheimer’s disease. Alzheimer’s disease and synucleinopathies have several things in common. In both, abnormal protein clumps build up in the brain for years before symptoms appear: amyloid and tau in Alzheimer’s disease and synuclein in Lewy body diseases. About half of people with Alzheimer’s-related amyloid and tau lumps also have synuclein lumps, which is why synucleinopathies are Alzheimer’s-related dementias. In addition, symptoms such as changes in thinking and behavior occur early in the course of the disease in both diseases.
Not all people with Lewy Body Disorder will have movement problems while sleeping before the onset of neurological symptoms. But studying people with REM sleep behavior disorder in the earliest stages of a neurodegenerative process can shed light on how abnormal clumps of protein cause brain damage, how various symptoms appear, and how the neurodegenerative process can be stopped or slowed down.
About the study
Nine clinical centers are participating in the study:
- Emory University
- Massachusetts General Hospital / Harvard Medical School
- Mayo Clinic
- Research Institute of the McGill University Health Center
- Stanford Medicine
- University of Minnesota
- Veterans Affairs Portland Health Care System
- Washington University Medical School in St. Louis
This study is supported by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke of the two National Institutes of Health (NIH) under grant number U19AG071754. This financing equals 100% of the total program costs. The authors are solely responsible for the content and do not necessarily represent the official views of the NIH.