People with a sleep disorder marked by the physical “acting out” of vivid dreams — a condition considered an early form of Parkinson’s disease — show changes in specific immune cells in the blood that directly relate to inflammation and damage to dopamine neurons in the brain, researchers report.
These changes were found in monocytes of people with what is called isolated REM sleep behavior disorder (iRBD), suggesting that interaction between these blood-borne immune cells and brain cells precedes Parkinson’s and might offer new ways of treating it via the blood.
Changes in monocytes, a type of immune white blood cell that helps to protect the body against viruses and other invaders, may also serve as a blood biomarker of brain health in people with Parkinson’s and like synucleinopathies, the researchers wrote.
“This is the first study to show that the body’s immune system continuously communicates with the brain during the development of Parkinson’s disease, and that changes in the body’s immune system influence the condition of the neurons in the brain,” Marina Romero-Ramos, PhD, a professor in the department of biomedicine at Aarhus University, in Denmark, said in a university press release.
Parkinson’s disease is characterized by a loss of dopamine neurons in a brain region called the substantia nigra, along with the toxic accumulation of the alpha-synuclein protein in clumps called Lewy bodies. These alterations activate immune cells in both the central (brain and spinal cord) and peripheral (outside the central) nervous system.
These immune cells have both a protective role, by clearing alpha-synuclein, and a disease-causing role, by inducing inflammation that’s tied to neurodegeneration.
iRBD, a condition that is frequently associated with Parkinson’s, is also thought to be an early predictor of the disease. People with iRBD have been shown to develop non-motor symptoms and brain dysfunction similar to that observed in Parkinson’s patients. As such, “iRBD provides a powerful tool for the study of early events in PD [Parkinson’s disease],” the researchers wrote.
Previous research by this team found that iRBD patients have increased immune activation in the substantia nigra, and reduced function of dopaminergic neurons in the putamen, a brain region also involved in Parkinson’s. Building on those findings, these scientists analyzed the blood of people from the earlier study, to identify proteins whose high levels in their immune cells correlated with markers of the neuronal inflammation and dysfunction observed in Parkinson’s.
“We know that Parkinson’s disease is characterized by an inflammation in the brain, and that this is crucial for the progression of the disease. But in the study, our interest has been focused on the immune cells found outside the brain,” Romero-Ramos said.
Levels of the proteins CD11b, CCR2, HLA-DR, CD163, and TLR4, all of which are expressed by monocytes, were assessed. All these proteins affect immune responses and inflammation, and have been linked to Parkinson’s disease.
In total, they analyzed blood samples from 15 iRBD patients (12 males, mean age of 65) and 22 healthy people serving as controls (all male, mean age of 64.4 ).
A significant increase in the proportion of mature natural killer immune cells — which defend the body against infection and tumor growth — was seen in iRBD patients relative to controls. The percentage of classical inflammatory monocytes was significantly higher in iRBD patients, while the percentage of nonclassical monocytes, which are largely anti-inflammatory — was lower.
The percentage of immune cells expressing CD11b and CCR2, previously linked to Parkinson’s, was also higher in the iRBD group. But levels of HLA-DR, whose mutations have been linked to a late-onset Parkinson’s risk, was lower in iRBD patients. Mutations in the HLA-DR gene functionally translate to increased HLA-DR expression on blood cells isolated from Parkinson’s patients who carry such mutations.
The researchers suggested that the decrease in HLA-DR levels observed in iRBD patients might be related to the proliferation and expansion of the classical monocyte population — that which is connected to inflammation — an event that is “especially relevant” in the early stages of Parkinson’s and other disorders associated with alpha-synuclein clumping.
Notably, in iRBD patients, high levels of immune cells expressing CD163 corresponded to lower immune activation in the substantia nigra and increased dopamine levels in the putamen, while high levels of TLR4 corresponded with impaired dopamine function in the putamen. These results suggest that CD163 may have a protective role and TLR4 a damaging role in iRBD and, potentially, in Parkinson’s disease.
“These findings support monocytes as biomarkers and potential targets,” the researchers wrote, adding that, “[f]uture studies should address possible association between monocytic changes and disease progression.”
Although the work is limited by the small number of participants and overrepresentation of males in both groups, the researchers said these results offer important insights into how Parkinson’s develops.
“This opens up the possibility of being able to design immunotherapy that modulates cells in the blood, which subsequently would stop or delay the changes in the brain. For the patients, being able to enjoy more years with good quality of life will be very significant,” Romero-Ramos said.
“This lays the foundation. We can continue to build on the study, because we’ve now discovered that there is a change in the blood at a very early stage of Parkinson’s disease, and that it’s related to changes in the brain. We didn’t have the data to truly say this before,” she added.
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