Estrogen-related receptor gene expression associates with sex differences in cortical atrophy in isolated REM sleep behavior disorder
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.
Authors
- Christina Tremblay (ORCID: https://orcid.org/0000-0002-7747-8147)
- Kaylena A. Ehgoetz Martens (ORCID: https://orcid.org/0000-0002-8488-2295)
- Jean‐Christophe Corvol (ORCID: https://orcid.org/0000-0001-7325-0199)
- Per Borghammer (ORCID: https://orcid.org/0000-0001-6391-8052)
- Luca Roccatagliata (ORCID: https://orcid.org/0000-0001-8029-3947)
- Marie Vidailhet (ORCID: https://orcid.org/0000-0002-2409-9143)
- Zsóka Varga (ORCID: https://orcid.org/0000-0001-7296-7382)
- Jean‐François Gagnon (ORCID: https://orcid.org/0000-0003-1132-0563)
- Elie Matar (ORCID: https://orcid.org/0000-0002-4994-0488)
- Shady Rahayel (ORCID: https://orcid.org/0000-0001-5786-3278)
- Allan K. Hansen (ORCID: https://orcid.org/0000-0002-3618-1558)
- Johannes Klein (ORCID: https://orcid.org/0000-0002-8553-2801)
- Ronald B. Postuma (ORCID: https://orcid.org/0000-0002-6468-4734)
- Véronique Daneault (ORCID: https://orcid.org/0000-0002-8950-9043)
- Pauline Dodet (ORCID: https://orcid.org/0000-0002-7078-8345)
- Petr Dušek (ORCID: https://orcid.org/0000-0003-4877-9642)
- Pietro Mattioli (ORCID: https://orcid.org/0000-0003-2563-5830)
- Stanislav Mareček (ORCID: https://orcid.org/0009-0004-0773-5373)
- Alexandre Pastor‐Bernier (ORCID: https://orcid.org/0000-0002-8865-6551)
- L. Churchill (ORCID: https://orcid.org/0009-0003-7150-4142)
- Karoline Knudsen (ORCID: https://orcid.org/0000-0002-0805-8659)
- Isabelle Arnulf (ORCID: https://orcid.org/0000-0002-2240-2516)
- Dario Arnaldi (ORCID: https://orcid.org/0000-0001-6823-6069)
- Simon J.G. Lewis (ORCID: https://orcid.org/0000-0002-4093-7071)
- Beatrice Orso (ORCID: https://orcid.org/0000-0001-9983-7940)
- Celine Haddad
- Marie Filiatrault
- Violette Ayral
- Stéphane Lehéricy
- Sleep assessment
- Genetic data
- Brain MRI data
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Centre National de la Recherche Scientifique (FR)
- The University of Sydney (AU)
- University of Waterloo (CA)
- Inserm (FR)
- Université du Québec à Montréal (CA)
- Charles University (CZ)
- Montreal General Hospital (CA)
- Aarhus University Hospital (DK)
- Sorbonne Université (FR)
- University of Oxford (GB)
- Institut Universitaire de Gériatrie de Montréal (CA)
- Hôpital du Sacré-Cœur de Montréal (CA)
- Ospedale Policlinico San Martino (IT)
- Institut du Cerveau (FR)
- Université de Montréal (CA)
- University of Genoa (IT)
- Macquarie University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-10
- DOI
- https://doi.org/10.1038/s41467-025-63829-w
- Citations
- 2
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.78
Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- Roche
- Sanofi
- Biogen
- Teva Pharmaceutical Industries
- Celgene
- AbbVie
- F. Hoffmann-La Roche
- Meso Scale Diagnostics
- Parkinsonforeningen
- Jascha Fonden
- EU Joint Programme – Neurodegenerative Disease Research
- Neurocrine Biosciences
- Denali Therapeutics
- Alzheimer Society
- National Institute for Health and Care Research
- Parkinson's UK
- European Commission
- Agence Nationale de la Recherche
- Ministerstvo Školství, Mládeže a Tělovýchovy
- Lundbeckfonden
- Parkinson Canada
- Agentura Pro Zdravotnický Výzkum České Republiky
- Servier
- H. Lundbeck A/S
- Parkinson Vereniging
- Genentech
- Allergan
- Sanofi Genzyme
- Avid Radiopharmaceuticals
- Canadian Institutes of Health Research
- Medical Research Council
- National Health and Medical Research Council
- Janssen Pharmaceuticals