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)-1ß, 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.

Plasma immune markers in an idiopathic REM sleep behavior disorder cohort.

INTRODUCTION: Increasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear. METHODS: We collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years. RESULTS: TNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01-1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47-11.81). CONCLUSIONS: Our study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.

Plasma cytokine profile in synucleinophaties with dementia.

Immune response may play a pivotal role in the pathogenesis of the common synucleinopathy as Parkinson's disease (PD) and could be mediated with the accumulation of neurotoxic alpha-synuclein. There is limited evidence for immune response in another synucleinopathy as dementia with Lewy bodies (DLB). Recent data suggest that immune response may contribute to cognitive impairment. We aimed to estimate plasma cytokine profile in patients with synucleinopathies with dementia (PD dementia (PDD), DLB). Plasma cytokine levels (interferon-gamma (IFN-gamma), interleukin (IL)-4 (IL-4), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1)). were estimated in 16 patients with DLB, 19 patients with PDD, 28 patients with PD without dementia (PD) and 19 individuals without neurological disorders (controls) using Luminex array system. Cognitive status was assessed with the Mini-Mental State Examination (MMSE). TNF-alpha and IL-6 plasma levels were elevated in patients with synucleinopathies with dementia (DLB, PDD) compared to controls and IL-10 plasma level was increased in PDD compared to controls (p < 0.05). IFN-gamma levels were decreased in PD and PDD patients compared to controls (p < 0.001, p = 0.026, respectively) and in PD patients than in DLB patients (p = 0.032). Patients with PD, PDD, and DLB were characterized by increased plasma levels of MCP-1 compared to controls (p < 0.001). At the same time, no differences in TNF-alpha, IL-10, IL-6 plasma levels in PD patients compared to controls were found. Our study demonstrated more pronounced immune response in synucleinopathies associated with dementia compared to PD without demetia.