Estrogen-related receptor gene expression associates with sex differences in cortical atrophy in isolated REM sleep behavior disorder

Marie Filiatrault, Violette Ayral, Christina Tremblay, Celine Haddad, Véronique Daneault, Alexandre Pastor-Bernier, Jean-François Gagnon, Ronald B. Postuma, Petr Dušek, Stanislav Mareček, Zsoka Varga, Johannes C. Klein, Michele T. Hu, Isabelle Arnulf, Pauline Dodet, Marie Vidailhet, Jean-Christophe Corvol, Stéphane Lehéricy, Simon Lewis, Elie Matar, Kaylena A. Ehgoetz Martens, Lachlan Churchill, Per Borghammer, Karoline Knudsen, Allan K. Hansen, Dario Arnaldi, Beatrice Orso, Pietro Mattioli, Luca Roccatagliata and Shady Rahayel ()
Additional contact information
Marie Filiatrault: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Violette Ayral: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Christina Tremblay: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Celine Haddad: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Véronique Daneault: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Alexandre Pastor-Bernier: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Jean-François Gagnon: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Ronald B. Postuma: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal
Petr Dušek: Charles University and General University Hospital
Stanislav Mareček: Charles University and General University Hospital
Zsoka Varga: Charles University and General University Hospital
Johannes C. Klein: University of Oxford
Michele T. Hu: University of Oxford
Isabelle Arnulf: Assistance Publique Hôpitaux de Paris
Pauline Dodet: Assistance Publique Hôpitaux de Paris
Marie Vidailhet: Assistance Publique Hôpitaux de Paris
Jean-Christophe Corvol: Assistance Publique Hôpitaux de Paris
Stéphane Lehéricy: Assistance Publique Hôpitaux de Paris
Simon Lewis: Macquarie University
Elie Matar: University of Sydney
Kaylena A. Ehgoetz Martens: University of Sydney
Lachlan Churchill: University of Sydney
Per Borghammer: Aarhus University Hospital
Karoline Knudsen: Aarhus University Hospital
Allan K. Hansen: Aarhus University Hospital
Dario Arnaldi: University of Genoa
Beatrice Orso: University of Genoa
Pietro Mattioli: University of Genoa
Luca Roccatagliata: IRCCS Ospedale Policlinico San Martino
Shady Rahayel: Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Isolated REM sleep behavior disorder, characterized by dream-enacting movements during REM sleep, is a male-predominant parasomnia and the strongest prodromal marker of synucleinopathies. Individuals with this disorder show cortical atrophy whose regional distribution covaries with gene expression patterns measured in the healthy human brain. However, the effect of sex on these brain changes remains unknown. The study objective is to comprehensively assess sex differences in cortical morphology and to characterize the healthy-brain gene expression correlates of brain abnormalities using the largest international multicentric MRI dataset of polysomnography-confirmed patients. Males have significantly more extensive and severe cortical thinning compared to females, despite similar age and clinical features. Imaging transcriptomics analyses indicate that regions affected in female patients map onto areas with higher expression of estrogen-related receptor genes, particularly ESRRG and ESRRA, in the healthy brain. These findings support potential sex-specific neuroprotection in the prodromal stages of synucleinopathies and may inform personalized and targeted therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-63829-w

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