Journal Article

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

Dušek, Petr, Borghammer, Per, Haddad, Celine, Arnaldi, Dario, Hansen, Allan K., Mareček, Stanislav, Pastor-Bernier, Alexandre, Klein, Johannes C., Gagnon, Jean-François, Filiatrault, Marie, Dodet, Pauline, Lehéricy, Stéphane, Postuma, Ronald B., Daneault, Véronique, Tremblay, Christina, Varga, Zsoka, Orso, Beatrice, Knudsen, Karoline, Corvol, Jean-Christophe, Roccatagliata, Luca, Rahayel, Shady, Ayral, Violette, Vidailhet, Marie, Arnulf, Isabelle, Matar, Elie, Churchill, Lachlan, Mattioli, Pietro, Ehgoetz Martens, Kaylena A., Hu, Michele T., Lewis, Simon

2025

Overview

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. This study reveals that females with isolated REM sleep behavior disorder show less neurodegeneration than males. The least affected regions in females are regions that overexpress estrogen-related genes, suggesting potential sex-specific neuroprotection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/61 / 59/57 / 631/114/2403 / 631/378/1689/364 / 692/699/375/1816 / 692/699/375/346/1718 / Abnormalities / Adult / Age / Aged / Alzheimer's disease / Atrophy / Atrophy - genetics / Behavior disorders / Biomarkers / Brain / Brain - diagnostic imaging / Brain - pathology / Cerebral Cortex - diagnostic imaging / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Disease / Estrogens / Female / Females / Gender differences / Gene expression / Genes / Humanities and Social Sciences / Humans / Magnetic Resonance Imaging / Male / Males / Medical imaging / Middle Aged / multidisciplinary / Neurodegeneration / Neuroimaging / Neuroprotection / Parkinson's disease / Polysomnography / Quality control / Receptors / Receptors, Estrogen - genetics / Receptors, Estrogen - metabolism / REM sleep / REM Sleep Behavior Disorder - diagnostic imaging / REM Sleep Behavior Disorder - genetics / REM Sleep Behavior Disorder - metabolism / REM Sleep Behavior Disorder - pathology / Science / Science (multidisciplinary) / Sex Characteristics / Sex differences / Sleep / Sleep disorders / Transcriptomics