Brain Iron Dysregulation in Iron Deficiency Anemia-Related Restless Leg Syndrome Revealed by Neuron-Derived Extracellular Vesicles: A Case-Control Study

Brain iron deficiency (ID) and, to a degree, systemic ID have been implicated in restless leg syndrome (RLS) pathogenesis. Previously, we found increased ferritin in neuron‐derived extracellular vesicles (NDEVs) in RLS, suggesting a mechanism for depleting intracellular iron by secreting ferritin‐loaded NDEVs. In this study, we hypothesized that increased NDEV ferritin occurs even in RLS accompanied by systemic ID and that neuronal intracellular iron depletion in RLS also manifests as NDEV abnormalities in other iron regulatory proteins, specifically, decreased transferrin receptor (TfR) and increased ferroportin. To address these hypotheses, we studied 71 women with ID anemia, 36 with RLS, and 35 without RLS. Subjects with RLS again showed higher NDEV ferritin and also decreased TfR, suggesting diminished neuronal capacity for iron uptake. Findings inform a more complete understanding of the pathogenic role of neuronal iron homeostasis and dissociate it from peripheral ID. ANN NEUROL 2024