Objective: Understanding the role of Neuron-derived extracellular vesicles (NDEVs) in the pathophysiology and as biomarkers of Restless Legs Syndrome (RLS).

Background: RLS is a sensorimotor disorder, characterized by an urge to move the legs, often linked to brain Iron deficiency (ID), despite normal peripheral iron levels. Previous research has demonstrated abnormal MRI-based brain iron determination and low cerebrospinal fluid (CSF) ferritin levels in RLS patients.

Method: A PubMed search was conducted using keywords, [restless legs syndrome], [Pathophysiology of RLS], [Iron Dysregulation in RLS], and [NDEVs in RLS]. Out of 1406 articles from the past 5 years, the most relevant studies were selected and analyzed.

Results: ID plays a significant role in the pathogenesis of RLS. NDEVs are membranous nanoparticles secreted by brain cells that are detected in the blood and are used in studies as potential sources of biomarkers for neurological disorders. . In a study conducted by Apostolos et al. on 71 women with ID anemia, where 36 had RLS. Subjects with RLS showed higher NDEV ferritin and decreased transferrin receptor (TfR), suggesting diminished neuronal capacity for iron uptake. Blood samples were collected for this case-control study and NDEVs were isolated via immunoaffinity capture. NDEV iron regulatory proteins were quantified for analysis which revealed altered brain iron metabolism at the cellular level. Increased NDEV ferritin levels suggest enhanced neuronal iron export, which has a major role in brain iron depletion. Also, decreased transferrin receptor (which decreases iron import into the cell) and increased ferroportin levels (which increases iron export from the cells), are reflected in NDEVs. The deviations in the homeostatic mechanisms of neuronal iron regulation cause NDEV abnormalities.

Conclusion: This review highlights the critical role of NDEVs in iron metabolism. NDEV as biomarkers can be explored as a diagnostic and therapeutic tool in RLS.

References: 1. Vlasie A, Trifu SC, Lupuleac C, Kohn B, Cristea MB. Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review). Exp Ther Med. 2022 Feb;23(2):185.
2. Chawla S, Gulyani S, Allen RP, Earley CJ, Li X, et al. Extracellular vesicles reveal abnormalities in neuronal iron metabolism in restless legs syndrome. Sleep. 2019 July 8;42(7):zsz079. doi:10.1093/sleep/zsz079
3. Manolopoulos A, York W, Pucha KA, Earley CJ, Kapogiannis D. Brain Iron Dysregulation in Iron Deficiency Anemia-Related Restless Leg Syndrome Revealed by Neuron-Derived Extracellular Vesicles: A Case-Control Study. Ann Neurol. 2024;96(3):560-564. doi:10.1002/ana.26941

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/neuron-derived-extracellular-vesicles-as-biomarkers-of-iron-dysregulation-in-restless-legs-syndrome-a-link-to-neurodegeneration/