A large international study involving nearly 700 participants reveals that women with a precursor condition to Parkinson's disease show significantly less brain atrophy—decreased cortical thickness in the brain—than men, despite similar clinical severity. This discovery, published in the journal Nature Communications, could lead scientists to explore the role that hormones might play in treating the disease.

Isolated REM sleep behavior disorder is characterized by violent movements during sleep, where people literally "act out" their dreams. Far from being harmless, this disorder is the most reliable early warning sign of neurodegenerative diseases caused by the accumulation of a toxic protein in the brain: more than 70% of affected individuals will eventually develop Parkinson's disease, Lewy body dementia, or, more rarely, multiple system atrophy (a disease affecting multiple body systems).

"This sleep disorder offers a unique window of opportunity to study the mechanisms of neurodegeneration before major motor or cognitive symptoms appear," explains Shady Rahayel, professor at UdeM's Faculty of Medicine and leader of this study.

The research team analyzed 888 brain scans from nine international centers in Canada, the Czech Republic, the United Kingdom, France, Australia, Denmark, and Italy.

After rigorous quality control, 687 participants were included in the final analysis: 343 patients with isolated REM sleep behavior disorder—or iRBD for isolated REM Sleep Behavior Disorder—and 344 healthy individuals.

The results are striking: while 37% of cortical areas showed significant atrophy in men with iRBD, only 1% of regions were affected in women. This difference persists despite similar age (around 67 years) and comparable clinical characteristics between men and 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," notes Marie Filiatrault, first author of the study and doctoral student at Université de Montréal.

To understand this protective phenomenon in women with iRBD, the researchers used an innovative approach that compares brain images with gene presence in different brain regions, measured in healthy brains studied after death.

The analysis revealed that brain regions less affected in women show increased expression of genes associated with estrogen function in the brain, notably the ESRRG and ESRRA genes, which produce estrogen-related hormone receptors. The ESRRG gene proved particularly interesting, as it is more highly expressed in the brain than in other body tissues.

These receptors play a crucial role in mitochondrial function (the cell's power plants), cellular energy production, and the survival of dopamine-producing neurons—precisely the cells that die in Parkinson's disease.

This discovery adds to a growing body of research demonstrating that women with neurodegenerative diseases benefit from certain brain protection, possibly through the action of estrogens and associated energy processes.

"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," emphasizes Shady Rahayel, who is also a researcher at the Center for Advanced Research in Sleep Medicine at Sacré-Cœur-de-Montréal Hospital.

Although only 25 to 40% of Parkinson's patients present iRBD symptoms, the research team focused on this precursor condition for a strategic reason: it allows observation of brain protection mechanisms before the appearance of major motor symptoms of Parkinson's.

"iRBD offers us a unique window to study these protective mechanisms in action at a very early stage, before too much damage is done in the brain," explains Professor Rahayel. Previous research has already shown that women with "classic" Parkinson's also benefit from similar protection, with generally slower progression than men.

The implications of this study are manifold. First, it underscores the importance of considering sex as a biological variable in clinical trials. The authors recommend separating men and women when randomly assigning participants to treatment groups, which could increase statistical power and reduce the number of participants needed.

Furthermore, the biological mechanisms identified—particularly those related to the ESRRG gene—could become promising therapeutic targets. Preclinical research has already demonstrated that greater ESRRG gene activity could protect dopamine-producing neurons against alpha-synuclein toxicity, a protein that accumulates abnormally in the brains of people with Parkinson's.

"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," concludes Professor Rahayel.