Marie Filiatrault, Violette Ayral, Christina Tremblay, Celine Haddad, Véronique Daneault, Alexandre Pastor‐Bernier, Jean‐François Gagnon, Ronald B. Postuma, Petr Dušek, Stanislav Mareček, Zsóka Varga, Johannes Klein, Michele T. Hu, Isabelle Arnulf, Pauline Dodet, Marie Vidailhet, Jean‐Christophe Corvol, Stéphane Lehéricy, ICEBERG Study Group, Sleep assessment, Genetic data, Brain MRI data, Stéphane Lehéricy, Stéphane Lehéricy, Simon J.G. Lewis, Elie Matar, Kaylena A. Ehgoetz Martens, L. Churchill, Per Borghammer, Karoline Knudsen, Allan K. Hansen, Dario Arnaldi, Beatrice Orso, Pietro Mattioli, Luca Roccatagliata, Shady Rahayel
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.