Women’s brains better protected from atrophy in REM disorder
Researchers see estrogen as likely reason for less damage vs. men
Women with isolated REM sleep behavior disorder (iRBD), an early sign of Parkinson’s disease, exhibit fewer signs of early brain deterioration than men of similar age and disease severity, a study showed.
The study, which analyzed the brains of almost 700 people with iRBD and healthy controls, found that women showed less severe and less widespread cortical atrophy – a thinning of the outer layer of the brain – in regions with higher levels of estrogen-related genes, those linked to female hormones.
“Our results suggest that certain brain areas in women with isolated REM sleep behavior disorder are better protected than those in men, likely through the action of estrogens,” Shady Rahayel, PhD, a professor at the university and leader of the study, said in a university news story.
The study, “Estrogen-related receptor gene expression associates with sex differences in cortical atrophy in isolated REM sleep behavior disorder,” was published in Nature Communications.
More than 70% of people with iRBD — a sleep disorder in which people act out their dreams physically and vocally — eventually develop neurodegenerative diseases, including Parkinson’s.
‘Window of opportunity’ for researchers
“This sleep disorder offers a unique window of opportunity to study the mechanisms of neurodegeneration before major motor or cognitive symptoms appear,” said Rahayel, who is also a researcher at the Center for Advanced Research in Sleep Medicine at Sacré-Cœur-de-Montréal Hospital.
The research team analyzed the brain scans of 687 participants, 343 with iRBD and 344 healthy people, matched for age, from nine international centers in Canada, Australia, and Europe. There was a lower proportion of women in the iRBD group than in controls (14% vs.86%).
Participants with iRBD had more severe motor symptoms and higher cognitive impairment, with no significant differences between men and women.
In men with iRBD, 37% of cortical areas showed significant atrophy (a decrease in cortical thickness), compared with 1% in women.
“Men show much more extensive and severe cortical thinning—the outer layer of the brain that controls our higher functions—than women, particularly in areas controlling movement and sensation, vision, and spatial orientation,” said Marie Filiatrault, first author of the study and a doctoral student at the university.
When the researchers compared brain images with the levels of certain genes in different brain regions, measured in healthy brains studied after death, they found that women had higher levels of the ESRRG and ESRRA genes, which produce receptors that bind estrogen, a key female sex hormone.
“These results suggest that regions where iRBD females show less cortical thinning overexpress genes enriched in … estrogen-related receptors,” the researchers wrote.
The team focused on the ESRRG gene, as it is more expressed in the brain than in other body tissues. The receptors play a crucial role in mitochondrial function and cellular energy production, as well as the survival of dopaminergic neurons — the nerve cells that are lost in Parkinson’s disease. Mitochondria are the energy-producing structures of cells.
Preclinical studies have shown that higher ESRRG gene activity may protect dopaminergic neurons from alpha-synuclein toxicity. Alpha-synuclein is a protein that abnormally accumulates in Parkinson’s brains.
Mechanisms related to the ESRRG gene could be promising therapeutic targets, the researchers said. “This study brings us closer to precision medicine where treatments could be tailored not only to the disease but also to individual biological characteristics, including sex,” Rahayel said.
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