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 alpha-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)-1 beta, IL-2, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-alpha). 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-alpha 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-alpha levels above the median showed a higher incidence of phenoconversion than those with lower TNF-alpha 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-alpha and phenoconversion risk in iRBD. Further studies are warranted to confirm the role of peripheral TNF-alpha in the pathogenesis of neurodegeneration in this disorder.