Women better protected against early Parkinson’s neurodegeneration, study finds

Women with an early precursor to Parkinson’s disease show much less brain shrinkage than men, despite similar disease severity, new research shows.

The discovery could help scientists explore how hormones might one day be used to treat the neurodegenerative condition.

The findings are based on data from nearly 700 participants across nine international research centres.

The study focused on isolated REM sleep behaviour disorder — a condition in which people physically act out their dreams.

It is considered the most reliable early warning sign of diseases caused by toxic protein build-up in the brain.

More than 70 per cent of those affected later develop Parkinson’s disease, Lewy body dementia or multiple system atrophy, which affects several body systems.

Researchers from Université de Montréal analysed 888 brain scans from centres in Canada, the Czech Republic, the UK, France, Australia, Denmark and Italy.

After quality checks, 687 participants were included: 343 patients with the sleep disorder and 344 healthy controls.

The results revealed clear sex-based differences.

While 37 per cent of the cortical areas — the brain’s outer layer responsible for higher functions — showed thinning in men, only one per cent of regions were affected in women.

This difference remained even though participants were of similar age (around 67) and had comparable clinical profiles.

Marie Filiatrault is first author of the study and a doctoral student at Université de Montréal.

The researcher said: “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 linked to movement, sensation, vision and spatial orientation.”

To understand the protective effect, researchers compared brain images with gene activity in different regions, measured in healthy brains after death.

They found that the less-affected areas in women showed higher expression of genes related to oestrogen function, particularly ESRRG and ESRRA, which produce oestrogen-related hormone receptors.

The ESRRG gene was especially notable, showing greater activity in brain tissue than elsewhere in the body.

These receptors play key roles in mitochondrial function — the cell’s energy production system — and in the survival of dopamine-producing neurons, the cells that die in Parkinson’s disease.

Shady Rahayel is professor at Université de Montréal’s Faculty of Medicine and lead author of the study.

Rahayel said: “This sleep disorder offers a unique window of opportunity to study the mechanisms of neurodegeneration before major motor or cognitive symptoms appear.

“Our results suggest that certain brain areas in women with isolated REM sleep behaviour disorder are better protected than those in men, likely through the action of oestrogens.”

The team chose to study this precursor condition because it allows observation of brain protection mechanisms before major motor symptoms develop.

Although only 25 to 40 per cent of people with Parkinson’s experience REM sleep behaviour disorder, studying this early stage gives insight into how the brain resists damage when it is still limited.

Previous studies have shown that women with established Parkinson’s disease tend to experience slower progression than men, pointing to similar protective effects.

The findings could shape future research and treatment development.

The authors recommend separating men and women in clinical trials, which could improve statistical accuracy and reduce the number of participants required.

The biological mechanisms identified — particularly those linked to the ESRRG gene — could also become potential therapeutic targets.

Early laboratory research suggests that increasing ESRRG activity may protect dopamine-producing neurons from the toxic effects of alpha-synuclein, a protein that builds up 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,” said Rahayel.