Sex Differences in Cerebrospinal Fluid Proteomics of Patients with Restless Legs Syndrome.

Abstract

Study objectives: The pathobiology of restless legs syndrome (RLS) remains poorly understood, complicating effective treatment. This observational cross-sectional study aimed to identify a cerebrospinal fluid proteomic signature of RLS and to explore sex-specific differences in cerebrospinal fluid proteomics.

Methods: Cerebrospinal fluid samples were collected from 22 untreated RLS patients and 18 controls, matched for age, body mass index, and sex. Proteomic analysis was conducted using the SOMAscan® platform, assessing over 7,000 peptides.

Results: Eight proteins were differentially abundant between patients and controls, with CRP and JAML increased, and TAPBPL and IL1RL1 decreased. Pathway analysis highlighted significant involvement in immune response, coagulation, and cytoskeletal regulation. Analyses were then carried out with sex stratification, comparing separately men and women. Sex-specific analyses revealed more pronounced proteomic alterations in males (68 differentially abundant proteins vs. control males) than females (17 proteins). Gene enrichment analysis revealed that men with RLS had more involvement of gene regulation and epigenetic factors than control males and women with restless legs syndrome had greater involvement of systemic inflammatory and vascular processes than control females.

Conclusions: This study identified a cerebrospinal fluid proteomic signature in RLS, implicating immune and inflammatory pathways in the disease's pathophysiology. Significant sex differences in protein level suggest potential sex-specific mechanisms in RLS, warranting further investigation. These findings contribute to the current understanding of RLS and could inform future therapeutic strategies.