Sleep disorder linked to neurodegeneration aim of NIH-funded grant

Neurosciences

Sleep disorder linked to neurodegeneration aim of NIH-funded grant

By
Susan Barber Lindquist

October 5, 2021

International team seeks hidden signs of brain damage in REM behavior disorder

ROCHESTER, Minn. — 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 Mayo Clinic, The Neuro (Montreal Neurological Institute-Hospital) of McGill University and Washington University School of Medicine in St. Louis has received a five-year grant expected to total $35.1 million to develop biomarkers for the disease. The biomarkers, a set of findings on specialized tests, will indicate:

Which people with the sleep disorder will go on to develop neurodegenerative diseases.
Which specific diseases will develop.
When symptoms will arise.
How quickly these diseases will progress.

The grant — from the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS), both part 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," says Yo-El Ju, M.D., a Washington University in St. Louis 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 disorder; 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 where dreaming occurs. Acting out dreams is an early sign that something in the brain is not functioning 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 may become available for clinical trials. But first scientists need to identify 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," says Bradley Boeve, M.D., 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."

Dr. Boeve, The Little Family Foundation Professor of Lewy Body Dementia at Mayo Clinic, and Dr. 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 people with rapid eye movement sleep behavior disorder and develop standardized tools to study them. More than 350 people with rapid eye movement sleep behavior disorder have enrolled in the consortium.

The new grant funds a larger study to identify biomarkers in these people and new participants. This larger study, called NAPS2, is led by Drs. Ju and Boeve, as well as Ronald Postuma, M.D., neurologist at The Neuro and the Research Institute of the McGill University Health Centre and co-principal investigator.

This study will follow approximately 430 participants with REM sleep behavior disorder and 60 people without sleep problems for five years. 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 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," says Mack Mackiewicz, Ph.D., a program director in the NIA Division of Neuroscience and 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 project oversight.

More than 2 million people in the U.S. and millions more around the world 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, and they share several similarities with Alzheimer's disease.

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 clumps of amyloid and tau related to Alzheimer's disease also have clumps of synuclein, which is why synucleinopathies are included among the dementias related to Alzheimer's disease. Symptoms such as changes in thinking and behavior occur early in the disease process in both conditions.

Not all people with Lewy body disorders have movement issues in their sleep before neurological symptoms begin. 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 neurodegeneration.

"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," Dr. Postuma says. "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 early Parkinson's people are in, so that better targeted therapies can be provided."

Nine clinical centers are participating in the study:

This study is supported by the NIA and NINDS under award number U19AG071754. This funding represents 100% of the total program costs. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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