A new clinical trial led by Jesse Cedarbaum, MD, professor of neurology, and David Hafler, MD, William S. and Lois Stiles Edgerly Professor of Neurology, is the first such study to test whether a drug can slow or prevent the onset of Parkinson’s disease in people at risk.

The first warning signs of Parkinson’s disease can manifest decades before the onset of motor problems. One of these is a sleep condition in which individuals act out their dreams, often violently. Known as rapid eye movement sleep behavior disorder (RBD), as many as 90% of cases will progress to Parkinson’s disease or a related brain disorder.

This years-long window between the development of RBD and the onset of Parkinson’s disease presents an opportunity to try and prevent the disorder before the motor symptoms arise. Research led by scientists at Yale School of Medicine on RBD and Parkinson’s disease suggests that inflammation in the spinal fluid may be contributing to the disease.

Now, in the new clinical trial, the researchers will investigate whether a drug called adalimumab (Humira), which is already used to treat inflammatory and autoimmune diseases, can prevent the emergence of Parkinson’s disease in individuals with RBD.

The study—An Exploratory Study of the Potential for Rational Immune System Manipulation to Prevent Emergence of Synucleinopathy Manifestations in Persons with REM Sleep Behavior Disorder, or “PRISMS” for short—recently enrolled its first participant. It is currently recruiting individuals between the ages of 50 and 80 with RBD across 15 participating sites in the United States and Canada.

“This is the first clinical trial of its kind to use an immunologically-based approach to try to slow the progression of Parkinson’s disease,” Cedarbaum says.

Rapid eye movement (REM) sleep is the phase of the sleep cycle in which the most vivid dreaming occurs. This phase gets its name because as we sleep, our eyes are moving behind our closed eyelids as they follow the action of the dream. The rest of our body, however, typically does not move because the healthy brain engages a mechanism that paralyzes the body from the eyes down. If you’ve ever seen a sleeping puppy whimper or twitch its paws, you’ve witnessed this in action—the partial movements are a result of the brain suppressing the body from fully acting out the dream.

However, in people with RBD, this dream paralysis mechanism stops working. The onset of RBD can put individuals and those around them at risk of injury—they might fall out of bed, for example, or kick and injure their bed partner. Clinicians have also reported instances of patients performing more typical, calmer activities such as drinking a cup of coffee or smoking a cigarette while they sleep.

In some cases, RBD has an identifiable cause. Some antidepressants, for example, can trigger the disorder. But in instances in which patients develop RBD seemingly out of the blue, called idiopathic or isolated RBD, they are at a significantly elevated risk for developing Parkinson’s disease or other brain diseases including dementia with Lewy bodies.

“People who come to see their doctor for the first time with RBD are at high risk of developing Parkinson’s disease or a related disorder at a rate of 6% per year,” Cedarbaum says. “The transition can happen anytime over a span of 15 to 20 years.”

Emerging evidence suggests that Parkinson’s disease may begin in the gut. All of our nerve cells contain a protein called alpha synuclein. Scientists have observed that the post-mortem brains of individuals who had Parkinson’s disease contain clumps of these proteins, which they refer to as “Lewy bodies.” They have also discovered clumps of synuclein in nerve cells in the gut, and that the protein clumps can spread to the brain in several different ways. The most common way is through the vagus nerve, which connects the brain to the stomach and intestines. Protein clumps can also begin forming in the olfactory bulb, which is why many people with Parkinson’s disease also report the loss of their sense of smell.

Once it reaches the brainstem, alpha synuclein begins to spread from nerve cell to nerve cell up the brain. Some of the first cells the protein hits are those that control paralysis during sleep, which is what causes RBD.

As synuclein continues to travel upwards, it reaches a region in the mid-brain called the substantia nigra. This region is part of the basal ganglia, a group of interconnected brain structures that help control movement. The substantia nigra transmits a chemical called dopamine higher up into the basal ganglia, and the impairment of this process causes the motor symptoms of Parkinson’s disease.

“Your brain has all these programs for making movements, and the basal ganglia is like the gearbox,” Cedarbaum explains. “Dopamine acts like oil. And when alpha synuclein damages the cells in the substantia nigra, they no longer make their dopamine oil, and movement gets slow, and sticky, and tremulous.”

Medications such as levodopa are effective in topping off the oil tank and suppressing Parkinson’s disease symptoms. However, they do not stop the trajectory of alpha synuclein as it continues to climb the brain, eventually impairing regions that control cognitive function and causing dementia. This progression can take as long as 20 years.

When a person develops RBD, it is an alarm bell that this pathological process is already underway.

“Because it takes so long for the whole process to develop, this represents a very opportune point in time at which to intervene and try to prevent the rest of the disease trajectory from happening,” Cedarbaum says.

The spread of synuclein appears to be only part of the story. Cedarbaum, a neurologist specializing in Parkinson’s disease, has spent much of his career trying to find interventions that prevent the death of dopamine-producing nerve cells. He was getting ready to retire when he was approached by Hafler, a world-renowned expert on multiple sclerosis. Hafler’s work has led to major advances in the treatment of the autoimmune disease and he hoped for similar success in finding new ways to treat Parkinson’s disease.

To Hafler, some of the features of RBD paralleled the early stages of multiple sclerosis. In 2021, he and Cedarbaum received a grant from the Aligning Science Across Parkinson’s (ASAP) network to study the underlying processes in people with RBD that lead to Parkinson’s disease. They conducted spinal taps on a large cohort of participants with RBD, Parkinson’s disease, and both conditions. They compared their findings with healthy controls, as well as patients with multiple sclerosis.

Their analyses detected elevated white blood cell counts, which is an indicator of inflammation, in the spinal fluid of participants with RBD. This inflammation wasn’t present in participants with Parkinson’s disease. And this trajectory is similar to that of multiple sclerosis, Hafler says.

“In the early autoimmune phase of multiple sclerosis, we see white blood cells in the spinal fluid,” Hafler explains. “But as the disease progresses, it’s no longer purely inflammatory, and more and more neurodegenerative changes appear.”

The researchers further analyzed the cells of the spinal fluid using single-cell RNA sequencing, which identified a specific cell in which genes contributing to inflammation were activated. These cells acted as receptors for a protein called tumor necrosis factor (TNF), which is also a driver of a number of autoimmune diseases including rheumatoid arthritis, ulcerative colitis, and Crohn’s disease.

“This gave us additional evidence that, at least in the early stages of Parkinson’s disease, inflammation, and, in particular, things related to TNF might be important,” says Cedarbaum.

Intriguingly, individuals with other autoimmune conditions like rheumatoid arthritis, Crohn’s disease, and ulcerative colitis are also at an increased risk for developing Parkinson’s disease, like people with RBD. But a medication that doctors used to treat these disorders, adalimumab, reduces risk to that of a healthy individual. This drug is an antibody that works by binding with TNF in the bloodstream and preventing it from causing inflammation in cells.

Based on this knowledge, the researchers wondered if adalimumab could also treat the inflammatory processes that contribute to Parkinson’s disease.

“We know that in the early stages of Parkinson’s disease, there’s a lot of inflammation,” says Ronald Postuma, MD, professor of neurology at McGill University and the principal investigator for the PRISMS study in Canada. “And so, if you tamp down the immune system, potentially you could prevent bystander damage—the immune cells attacking cells that it should not be attacking.”

The PRISMS study is a Yale-led clinical trial that spans across 14 centers (including Yale) in the United States and one in Canada that are part of the Parkinson Study Group, a consortium of academic centers that has run over 100 clinical trials in Parkinson’s disease and related disorders over the last 40 years. The clinical trial coordinating center is at the Center for Health Technology at the University of Rochester.

To enroll, candidates must have a confirmed diagnosis of RBD through a polysomnography, or sleep study. To increase the likelihood that alpha synuclein clumping is the underlying cause of candidates’ RBD, researchers will also evaluate them for hyposmia, or loss of sense of smell. Typically, scientists check for Lewy bodies through either a spinal tap or skin biopsy, both of which are invasive procedures. However, studies show that individuals with both RBD and smell loss, which researchers can test for non-invasively, have at least a 90% chance of having this alpha synuclein pathology. Candidates must have both RBD and hyposmia to be eligible for the study.

Once enrolled, participants will either give themselves an injection of adalimumab or a placebo every two weeks for two years. Participants will visit their clinical site about nine times during the trial to answer questions about their health and undergo various tests to evaluate movement patterns and cognition. Researchers will also take blood samples during site visits to test immune cell function and look for proteins related to Parkinson’s disease. Once a year, they will ask about half of participants to undergo a spinal tap so they can look for any changes in the spinal fluid, including whether there is aggregation of alpha synuclein.

Participants will undergo three different brain scans each year. Two of the scans, including a magnetic resonance imaging (MRI) scan, will test for impairment in the brain’s dopamine system. A third scan will measure how the brain uses a small, safe amount of radioactive sugar. This is because the brains of people with Parkinson’s disease show abnormal patterns of energy use in specific regions, which appear years before the motor symptoms of the disorder manifest and steadily worsen.

“If our drug prevents worsening of this pattern, or the loss of dopamine signal, we will have a hint that the drug is working,” Cedarbaum says.

All drugs have side effects. There are risks associated with taking adalimumab, such as a higher risk of certain infections including hepatitis and tuberculosis. The drug is also associated with a slightly higher risk of certain cancers and neurological problems that have symptoms similar to multiple sclerosis. The researchers will closely monitor participants for complications during the study.

Currently available therapies for Parkinson’s disease are effective in reducing its symptoms but fail to stop it from progressing. The researchers are excited not only to try to identify a treatment that targets the underlying disease processes, but also to intervene before motor symptoms first occur.

“In the multiple sclerosis world, if we treat the disease very early, it is 98% effective in stopping the disease,” Hafler says. “We hope to achieve something similar with Parkinson’s disease. It’s all about recognizing a disease and treating it early.”

The team hopes the PRISMS study will inspire more research to identify new medications for Parkinson’s disease. They plan to run similar clinical trials with different drugs to identify other promising candidates. “Finding anything that will slow down the progression to the serious stages of the disease would really be a game changer,” Postuma says.

The study also highlights the importance of interdisciplinary collaboration. “When we cross specialty lines, and movement disorder neurologists start working with sleep neurologists and immunologists, that’s when we start seeing potential breakthroughs in science and medicine,” Cedarbaum says.

The PRISMS study is funded by grants from the Marcus Foundation and the National Institute on Aging. More information about the trial, including eligibility requirements, site locations, and an outline of the study protocol, can be found on clinicaltrials.gov and on the study’s webpage.