Serum TNF-α and neurodegeneration in isolated REM sleep behavior disorder

Objective To investigate serum inflammatory cytokine profiles in patients with isolated REM sleep behavior disorder (iRBD) and to explore whether these markers are associated with phenoconversion risk to α-synucleinopathies. Methods In this prospective cohort study, we analyzed serum samples from patients with polysomnography-confirmed iRBD (n = 30) and healthy controls (n = 12). We measured the following cytokines: interleukin (IL)-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-α (TNF-α). All patients underwent motor and non-motor evaluations and dopamine transporter imaging at baseline for predicting the phenoconversion risk. We followed the patients quarterly over up to 6 years to identify disease conversion. We also assessed longitudinal changes in cytokine levels from baseline at the 2- and 4-year follow-up visits. Results The baseline cytokine levels did not differ between the patients and controls. However, the TNF-α levels were significantly increased in a subgroup of the patients with multiple markers (≥3) for phenoconversion risk compared to those without (p = 0.008) and controls (p = 0.003). At longitudinal analyses, patients with TNF-α levels above the median showed a higher incidence of phenoconversion than those with lower TNF-α levels (47% vs. 7%; p = 0.008), and this significant association persisted after adjusting for covariates (p = 0.026). The cytokine levels over 4 years of follow-up period did not change significantly. Conclusions Our data suggest a possible link between serum TNF-α and phenoconversion risk in iRBD. Further studies are warranted to confirm the role of peripheral TNF-α in the pathogenesis of neurodegeneration in this disorder.