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.

Centre for Advanced Research in Sleep Medicine Hôpital du Sacré Cœur de Montréal Quebec Integrated University Centre for Health and Social Services of Northern Island of Montreal Montreal QC Canada

Department of Health Sciences University of Genova Genova Italy

Department of Kinesiology and Health Sciences University of Waterloo Waterloo ON Canada

Department of Medicine University of Montreal Montreal QC Canada

Department of Neurology and Centre of Clinical Neurosciences 1st Faculty of Medicine Charles University and General University Hospital Prague Czechia

Department of Neurology Montreal General Hospital Montreal QC Canada

Department of Neuroscience Rehabilitation Ophthalmology Genetics Maternal and Child Health Clinical Neurology University of Genoa Genoa Italy

Department of Neuroscience University of Montreal Montreal QC Canada

Department of Nuclear Medicine and PET Aarhus University Hospital Aarhus Denmark

Department of Psychology Université du Québec à Montréal Montreal QC Canada

Department of Psychology University of Montreal Montreal QC Canada

Faculty of Medicine and Health University of Sydney Camperdown NSW Australia

IRCCS Ospedale Policlinico San Martino Genoa Italy

Oxford Parkinson's Disease Centre and Division of Neurology Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK

Parkinson's Disease Research Clinic Macquarie Medical School Macquarie University Sydney NSW Australia

Research Centre Institut universitaire de gériatrie de Montréal Montreal QC Canada

Sorbonne University Institut du Cerveau Inserm CNRS Assistance Publique Hôpitaux de Paris Paris France

The Neuro McGill University Montreal Canada QC

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