Serum Ferritin and Inflammation in Isolated REM Sleep Behavior Disorder: A Longitudinal Study.

Abstract

Isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of α-synucleinopathies. Iron metabolism and inflammation have been implicated in the pathogenesis of neurodegeneration. This study investigated the peripheral iron metabolism and inflammation in relation to prodromal clinical features and disease progression in iRBD. This prospective observational cohort study recruited patients with iRBD at Sleep Medicine Center of West China Hospital. We measured peripheral iron metabolism markers and analyzed their associations with clinical characteristics; REM sleep without atonia (RSWA); and inflammatory markers including C-reactive protein (CRP), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α. Patients with iRBD were further stratified based on sex-specific ferritin levels. Cox regression was used to assess the risk of neurodegenerative diseases. A total of 113 patients with iRBD (65.33 ± 6.80 years, 23.1% female) and 99 healthy controls (HCs) (64.92 ± 7.12 years, 22.1% female) were enrolled. Patients with iRBD showed dysregulated iron metabolism, with particularly elevated serum ferritin levels compared with HCs (338.48 ± 200.16 vs 238.73 ± 129.50, <i>p</i> < 0.001). Serum ferritin was positively associated with RBD symptom severity, autonomic dysfunction, olfactory impairment, motor symptoms, and RSWA. In the longitudinal analysis, 79 patients with iRBD were included, with a follow-up duration of 4.06 ± 2.1 years. During this period, 23 patients (29.1%) developed neurodegenerative diseases. In a Cox regression model adjusted for age and sex, elevated ferritin levels were significantly associated with an increased risk of phenoconversion (hazard ratio 2.91, 95% CI 1.06-7.99, <i>p</i> = 0.038). Patients with iRBD with high ferritin demonstrated increased IL-10 (3.21 ± 1.71 vs 2.53 ± 1.24, <i>p</i> = 0.029) and TNF-α (4.27 ± 3.41 vs 2.77 ± 2.38, <i>p</i> = 0.046) levels. Serum ferritin levels were positively correlated with CRP (<i>r</i> = 0.204, <i>p</i> = 0.003) and TNF-α (<i>r</i> = 0.160, <i>p</i> = 0.020). This study showed the dysregulation of peripheral iron metabolism in patients with iRBD. Elevated serum ferritin was associated with a more severe prodromal neurodegenerative phenotype in iRBD. Furthermore, our findings indicate that peripheral iron metabolism potentially correlates with inflammation in the neurodegeneration of iRBD.