$ 35.1 million US grant focuses on studying sleep disorders linked to neurodegeneration

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People with REM sleep behavior disorder make their dreams come true. While they are sleeping safely in bed, for example, they may 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 the condition have a 50-80% chance of developing severe neurodegenerative disease within a decade of diagnosis.

An international team led by researchers from The Neuro (Montreal Neurological Institute-Hôpital) at McGill University, Washington University School of Medicine in St. Louis, Mayo Clinic in Rochester, Minnesota, received a grant from five years that is expected to total US $ 35.1 million to develop biomarkers that indicate which people with sleep disorders will develop neurodegenerative diseases, which specific diseases, 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 from the US National Institutes of Health (NIH) -; will help lay the groundwork for clinical trials focused on stopping bothersome disease from progressing to debilitating disease.

REM sleep behavior disorder is linked to Parkinson’s disease, a condition of movement; Lewy body dementia, which causes cognitive decline; and multisystem atrophy, in which the ability to regulate involuntary functions such as blood pressure, respiration, and bladder and bowel function deteriorates.

The most important goal of this research is to find ways to reliably identify early-onset Parkinson’s disease, Lewy body dementia, and multisystem atrophy. When we do this, we can start planning trials to prevent disease. So far, we have very good clinical predictors of the disease, but biomarker research has still caught up. Biomarkers are important to help define precisely what stage of disease people are in, so that better targeted therapies can be provided. “

Dr. Ronald Postuma, Co-Principal Investigator, The Neuro and the Research Institute, McGill University Health Center

“The chances that people with REM sleep behavior disorder will develop neurodegenerative disease are quite alarming, and there is currently no treatment to reduce this risk,” said Dr Yo-El Ju, neurologist at the ‘University of Washington and Co-Principal Investigator. “We have no way of predicting if and how soon a person will develop any of these diseases or which they will get. And we certainly don’t know how to prevent it.”

Normally, people are paralyzed during REM sleep, the phase of sleep in which dreams occur. Dreaming is an early sign that something in the brain isn’t working quite the way it should. REM sleep behavior disorder is linked to diseases caused by an accumulation of abnormal clumps of the alpha-synuclein protein in the brain. Such clumps often unite at the onset of disease in a part of the brain that paralyzes the body during REM sleep. As this area gets damaged, people start to struggle while they are dreaming.

Several drugs and immunotherapies targeting alpha-synuclein are in development and 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 when and what type of synucleinopathy disorder is almost certainly hidden in one or more of the biomarkers that will be assessed in this study,” said Dr Bradley Boeve, neurologist at the Mayo Clinic and co. – principal investigator of the grant. . “If we can identify biomarkers that predict the future, then we can focus on those biomarkers for future clinical trials designed to delay onset or prevent dementia or parkinsonism.”

The NAPS consortium

Dr Boeve, Professor of Lewy Body Dementia at the Little Family Foundation at the Mayo Clinic, and Dr Ju, Barbara Burton and Reuben Morriss III Professor of Neurology at the University of Washington, founded the North American Consortium of prodromal synucleinopathy (NAPS) in 2018 to pull together a group of people with REM sleep behavior disorders and develop standardized tools to study them. More than 350 people with REM sleep behavior disorders have joined the NAPS consortium. The new grant funds a larger study to identify biomarkers in these people as well as new participants.

This larger study, called NAPS2, is being led by Drs Ju, Boeve and Postuma. This study will follow, for five years, approximately 430 participants with REM sleep behavior disorders and 60 people without sleep problems. Patients and control participants will undergo regular comprehensive clinical examinations and nighttime sleep studies. They will also provide samples of blood and, if desired, cerebrospinal fluid. Participants with REM sleep behavior disorders will also have brain scans.

“NAPS2 is another example of the coordinated and collaborative support NIH provides to advance discoveries and understanding of devastating brain disorders,” said Mack Mackiewicz, PhD, program director at the NIA Division of Neuroscience and scientist for the NIA project on the grant. “This project, which considers sleep a risk factor for dementia, is just one example of the wide range of research that NIH is funding into neurodegenerative diseases.” The NIA and NINDS fund NAPS2 equally with a joint scientific contribution and the NIA is leading the supervision of the project.

About Lewy Body Disorders

More than two million people in the United States live with Lewy Body Disorders, a group of diseases caused by buildup of alpha-synuclein in their brains. These synucleinopathies include Lewy body dementia, Parkinson’s disease, and multisystem atrophy. Collectively, they are the second most common type of neurodegenerative disease after Alzheimer’s disease. Alzheimer’s disease and synucleinopathies share several similarities. In both cases, abnormal protein clumps accumulate in the brain for years before any symptoms occur: amyloid and tau in Alzheimer’s disease and synuclein in Lewy body disorders. About half of people with amyloid clusters and tau linked to Alzheimer’s disease also have synuclein clusters, which is why synucleinopathies are included among dementias linked to Alzheimer’s disease. Additionally, symptoms such as changes in thinking and behavior occur early in the disease process in both types of conditions.

Not all people with Lewy body disorders have movement problems in their sleep until neurological symptoms appear. But studying people with REM sleep behavior disorder, in the early stages of a neurodegenerative process, may provide insight into how abnormal protein clumps lead to brain damage, the appearance of different symptoms, and how to stop or slow down the neurodegenerative process.

About the study

Nine clinical centers are participating in the study:

  • Emory University
  • Massachusetts General Hospital / Harvard School of Medicine
  • Mayo Clinic
  • Research Institute of the McGill University Health Center
  • Stanford Medicine
  • UCLA
  • University of Minnesota
  • Portland Veterans Health Care System
  • Washington University School of Medicine in St. Louis

This study is supported by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, both of the National Institutes of Health (NIH) under award number U19AG071754. This funding represents 100% of the total cost of the program. The contents are the sole responsibility of the authors and do not necessarily represent the official opinions of the NIH.

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