Estrogen-related receptor genes underlie sex differences in cortical atrophy associated with isolated REM sleep behavior disorder

Isolated REM sleep behavior (iRBD) is a male predominant parasomnia characterized by abnormal dream-enacting movements in REM sleep. It is the prodromal manifestation most strongly associated with the development of synucleinopathies, such as Parkinsons disease or dementia with Lewy bodies. While individuals with iRBD exhibit significant cortical atrophy shaped by distinct gene expression, sex-specific differences in structural brain changes remain unknown. In this study, we investigate the effect of sex on brain atrophy in iRBD and examine the gene expression underpinning the brain abnormalities in a large international multicentric MRI dataset with polysomnography-confirmed iRBD. T1-weighted scans from 408 individuals with iRBD and 480 healthy controls were acquired. Vertex-based cortical surface reconstruction and segmentation were conducted, and general linear models were used to quantify brain atrophy and assess the sex effect on cortical thickness in iRBD compared to controls. We then used a high resolution parcellation to further characterize the sex differences and conduct imaging transcriptomics analyses. Gene enrichment analyses were performed to identify genes associated with sex differences in cortical atrophy in iRBD. Males with iRBD showed significantly more cortical thinning compared to females with iRBD and controls, despite similar age and clinical features. The gene enrichment analysis revealed that female-specific resilience in cortical atrophy was associated with overexpression of oestrogen-related receptors. These findings provide mechanistic insight of sex-specific neuroprotection in prodromal stages of synucleinopathies, highlighting the critical impact of sex on the progression of neurodegenerative diseases.