People with rapid eye movement (REM) sleep behavior disorder act out their dreams. While sleeping safely in bed, for example, they might throw up their arms to catch an imaginary ball or try to run from an illusory assailant. Such actions are more than just a nuisance. People with the disorder have a 50% to 80% chance of developing a serious neurodegenerative disease within a decade of diagnosis.
An international team led by researchers at Washington University School of Medicine in St. Louis, Mayo Clinic in Rochester, Minn., and The Neuro (Montreal Neurological Institute-Hospital) of McGill University has received a five-year grant expected to total $35.1 million to develop biomarkers that indicate which people with the sleep disorder will go on to develop neurodegenerative diseases, which specific diseases, when symptoms will arise, 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 of the National Institutes of Health (NIH) — will help lay the groundwork for clinical trials focused on stopping the troublesome condition from progressing into a debilitating disease.
“The odds of people with REM sleep behavior disorder developing a neurodegenerative disease are pretty alarming, and currently there are no treatments to decrease that risk,” said Yo-El Ju, MD, a Washington University neurologist and co-principal investigator. “We have no way of predicting whether and how soon someone will develop one of these diseases or which one they will get. And we certainly don’t know how to prevent it.”
REM sleep behavior disorder is linked to Parkinson’s disease, a movement condition; dementia with Lewy bodies, which 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.
Normally, people are paralyzed during REM sleep, the phase of sleep in which dreaming occurs. Acting out dreams is an early sign that something in the brain is not functioning quite as it should. REM sleep behavior disorder is connected to diseases caused by an accumulation of abnormal clumps of the protein alpha-synuclein in the brain. Such clumps often coalesce early in the course of the diseases in a part of the brain that paralyzes the body during REM sleep. As that area becomes damaged, people start thrashing around as they dream.
Several drugs and immunotherapies targeting alpha-synuclein are being developed, and they may become available for clinical trials in REM sleep behavior disorder. But first, scientists need to identify a set of findings on specialized tests, or biomarkers, of impending neurological disease in people with REM sleep behavior disorder.
“Information that predicts the timing and type of synucleinopathy disorder is almost certainly hidden in one or more of the biomarkers that will be assessed as part of this study,” said Bradley Boeve, MD, a Mayo Clinic neurologist and the grant’s co-principal investigator. “If we can identify biomarkers that predict the future, we can then focus on these biomarkers for upcoming clinical trials designed to delay the onset of or prevent dementia or parkinsonism.”
Boeve, The Little Family Foundation Professor of Lewy Body Dementia at Mayo Clinic, and Ju, the Barbara Burton and Reuben Morriss III Professor of Neurology at Washington University, founded the North American Prodromal Synucleinopathy (NAPS) Consortium in 2018 to pull together a group of people with REM sleep behavior disorder and develop standardized tools to study them. More than 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 led by Ju, Boeve and co-principal investigator Ronald Postuma, MD, of The Neuro and the Research Institute of the McGill University Health Centre. This study will follow, for five years, about 430 participants with REM sleep behavior disorder and 60 people without sleep problems. Patients and control participants will undergo regular comprehensive clinical exams and overnight sleep studies. They also will provide samples of blood and, if willing, cerebrospinal fluid. Participants with REM sleep behavior disorder also will undergo brain scans.
“NAPS2 is another example of the coordinated and collaborative support NIH provides to foster discoveries and understanding of devastating brain disorders,” said Mack Mackiewicz, PhD, a program director in the NIA Division of Neuroscience and the NIA project scientist on the grant. “This project, looking at sleep as a risk factor for dementia, is just one example of the broad spectrum of research NIH is funding on neurodegenerative diseases.”
NIA and NINDS are funding NAPS2 equally with joint scientific input and NIA leading the project oversight.
More than 2 million people in the U.S. are living with Lewy Body disorders, a group of diseases caused by clumps of alpha-synuclein in their brains. These so-called synucleinopathies include dementia with Lewy bodies, Parkinson’s disease, and multiple system atrophy. Collectively, they are the second most common kind of neurodegenerative diseases after Alzheimer’s disease.
Alzheimer’s disease and synucleinopathies share several similarities. In both, abnormal clumps of proteins accumulate in the brain for years prior to any symptoms: amyloid and tau in Alzheimer’s disease, and synuclein in Lewy body disorders. About half of people with Alzheimer’s disease-related clumps of amyloid and tau also have clumps of synuclein, which is why synucleinopathies are included among the Alzheimer’s disease-related dementias. In addition, symptoms such as changes in thinking and behavior occur early in the disease process in both kinds of conditions.
Not all people with Lewy Body disorders have movement issues in their sleep prior to the onset of neurological symptoms. But studying people with REM sleep behavior disorder, at the earliest stages of a neurodegenerative process, may yield insight into how abnormal protein clumps lead to damage to the brain, how different symptoms arise, and how to stop or slow the neurodegenerative process.
“The most important goal of this research is to find ways to reliably identify early Parkinson’s disease, Lewy body dementia and multiple system atrophy,” Postuma said. “When we do this, we can start planning trials to prevent disease. So far, we have very good clinical predictors of disease, but biomarker research has still been catching up. Biomarkers are important to help precisely define what stage of disease people are in so that better targeted therapies can be provided.”
Nine clinical centers are participating in the study: Emory University, Massachusetts General Hospital/Harvard Medical School, Mayo Clinic, McGill University Health Centre Research Institute, Stanford Medicine, UCLA, University of Minnesota, Veterans Affairs Portland/Oregon Health Sciences University and Washington University.