Parkinson’s trial targets inflammation before motor symptoms emerge
PRISMS is enrolling adults with REM sleep behavior disorder in US and Canada
Written by |
- PRISMS is testing whether targeting early inflammation can prevent or slow Parkinson’s before motor symptoms emerge.
- Participants are adults ages 50 to 80 with REM sleep behavior disorder and a reduced sense of smell.
- Researchers are testing adalimumab or placebo injections every two weeks for two years.
A new clinical trial led by scientists at the Yale School of Medicine is testing whether targeting inflammation in people at high risk of Parkinson’s disease can prevent or slow disease development.
In the PRISMS study (NCT06996652), which recently enrolled its first participant, researchers are testing adalimumab, an anti-inflammatory medication sold under the brand name Humira and approved for several autoimmune and inflammatory diseases.
RBD may offer an early window for intervention
The study is recruiting adults ages 50 to 80 with REM sleep behavior disorder (RBD) at several sites across the U.S. and Canada. RBD causes people to act out their dreams, sometimes violently, and can develop years before Parkinson’s disease or a related disorder.
“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,” Jesse Cedarbaum, MD, professor at Yale School of Medicine and the study’s lead investigator, said in a university news story.
Parkinson’s disease is caused by the loss of nerve cells that produce dopamine, a chemical messenger that helps control movement. These cells are primarily located in a region of the brain called the substantia nigra. As these cells are lost and dopamine signaling is disrupted, motor symptoms such as tremor, rigidity, and slowed movements can develop.
Exactly what triggers the loss of these nerve cells is not fully understood, but several processes may contribute. These include abnormal clumping of a protein called alpha-synuclein and neuroinflammation, or inflammation in the brain.
Current treatments can ease Parkinson’s symptoms, but they do not stop the disease from progressing. That has increased interest in identifying Parkinson’s-related changes earlier, before substantial nerve cell loss has occurred, and testing treatments that could change the course of the disease. RBD may offer one such opportunity for earlier intervention.
“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 said. “The transition can happen anytime over a span of 15 to 20 years.”
Alpha-synuclein may connect RBD and Parkinson’s
The connection between RBD and Parkinson’s may involve the clumping of a protein called alpha-synuclein. According to the researchers, these protein clumps may first form outside the brain, potentially in the gut, and then spread into the brain. They may reach areas involved in controlling paralysis during sleep and, as the disease process progresses, spread to the substantia nigra, a region involved in movement. RBD may be a sign that this process is already underway, even before Parkinson’s motor symptoms appear.
In previous research, the Yale team found higher numbers of white blood cells — a sign of inflammation — in the spinal fluid of people with RBD, but not in people with Parkinson’s. Further analysis identified a specific type of cell in which inflammation-related genes were activated and pointed to a possible role for tumor necrosis factor (TNF), an inflammatory protein involved in several autoimmune diseases.
“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,” Cedarbaum said.
These findings led the researchers to investigate whether adalimumab, an antibody-based therapy that blocks TNF activity, could delay or prevent neurological changes associated with Parkinson’s.
“We know that in the early stages of Parkinson’s disease, there’s a lot of inflammation,” said Ronald Postuma, MD, professor at McGill University and 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 they should not be attacking.”
PRISMS requires RBD and a reduced sense of smell
To be eligible for the PRISMS study, participants must have RBD confirmed by a sleep study and hyposmia, or a reduced sense of smell. According to the researchers, people with both RBD and hyposmia have a high likelihood of underlying alpha-synuclein clumping.
Participants will give themselves an under-the-skin injection of adalimumab or a placebo every two weeks for two years. During the study, researchers will monitor their health through clinical assessments, blood tests, and tests of movement and cognitive function.
Participants will also undergo brain scans to assess the brain’s dopamine system and how it uses energy. About half of participants will undergo a spinal tap once a year so researchers can look for changes in the spinal fluid, including alpha-synuclein aggregation.
Because adalimumab suppresses the immune system, participants will be closely monitored for side effects, including an increased risk of certain infections and other known risks associated with the medication.
The researchers hope that targeting inflammation at this early stage — before Parkinson’s motor symptoms emerge — could change the course of the disease rather than only treating its symptoms.
“Finding anything that will slow down the progression to the serious stages of the disease would really be a game changer,” Postuma said.
Leave a comment
Fill in the required fields to post. Your email address will not be published.