Highlights
- Elevated serum ferritin is a consistent biomarker of iron dysregulation and correlates with more severe prodromal features in isolated REM sleep behavior disorder (iRBD).
- Increased peripheral inflammation markers, especially IL-10 and TNF-α, associate with high ferritin levels, highlighting a potential link between iron metabolism and neuroinflammation.
- Longitudinal data demonstrate that elevated ferritin independently predicts phenoconversion from iRBD to overt α-synucleinopathies, positioning ferritin as a valuable prognostic biomarker.
Background
Isolated REM sleep behavior disorder (iRBD) is increasingly recognized as an early prodromal phase of α-synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Characterized by REM sleep without atonia (RSWA) and dream enactment behaviors, iRBD patients often present subtle non-motor symptoms such as autonomic dysfunction and olfactory impairment prior to overt neurodegeneration. Early identification of biomarkers predicting phenoconversion holds paramount importance for timely intervention and mechanistic understanding.
Iron metabolism dysregulation and chronic inflammation have been implicated as mechanistic contributors in neurodegenerative disorders. Serum ferritin, a key intracellular iron storage protein reflective of systemic iron status and acute-phase inflammatory responses, has garnered attention for its potential as a peripheral biomarker. However, its role, alongside other inflammatory markers, in the prodromal stages of α-synucleinopathies such as iRBD remains under-investigated.
Key Content
Evidence from Cross-Sectional and Longitudinal Studies in iRBD
The landmark longitudinal study by Yin et al. (2026) enrolled 113 patients with polysomnography-confirmed iRBD and 99 matched healthy controls (HCs) to investigate peripheral iron metabolism and inflammatory markers. iRBD patients displayed significantly elevated serum ferritin compared to HCs (mean 338.48 ± 200.16 vs. 238.73 ± 129.50 ng/mL, p < 0.001), suggesting systemic iron metabolism perturbation in the prodromal phase.
Serum ferritin correlated positively with the severity of RBD symptoms (clinical motor and non-motor features), autonomic dysfunction, olfactory impairment, motor symptoms, and degree of RSWA measured by polysomnography indices. These findings emphasize the potential of ferritin as a biomarker reflecting the burden of prodromal neurodegeneration.
Longitudinal follow-up (mean 4.06 ± 2.1 years) of 79 iRBD patients revealed that nearly 29% converted to clinically manifest neurodegenerative diseases, predominantly PD or DLB. In multivariate Cox regression models adjusted for age and sex, patients with ferritin levels above sex-specific thresholds faced a nearly threefold increased risk of phenoconversion (hazard ratio 2.91, 95% CI 1.06–7.99, p = 0.038). This identifies serum ferritin as an independent predictor of neurodegenerative progression in iRBD.
Interrelationship Between Iron Metabolism and Inflammation in iRBD
The study further explored systemic inflammation by measuring blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-α). Patients stratified with high ferritin demonstrated statistically significant elevations in anti-inflammatory IL-10 (3.21 ± 1.71 vs. 2.53 ± 1.24 pg/mL, p = 0.029) and pro-inflammatory TNF-α (4.27 ± 3.41 vs. 2.77 ± 2.38 pg/mL, p = 0.046) compared to those with lower ferritin. Moreover, serum ferritin positively correlated with CRP (r = 0.204, p = 0.003) and TNF-α (r = 0.160, p = 0.020), implicating ferritin as a potential nexus between iron dysregulation and systemic inflammation.
These findings align with broader neurodegenerative research implicating neuroinflammation and oxidative stress driven by iron overload in exacerbating α-synuclein aggregation and neuronal injury. The bidirectional interplay between peripheral iron homeostasis and inflammatory signaling may inform novel therapeutic targets.
Comparative Evidence in Neurodegeneration
Accumulating evidence in Parkinson’s disease and related synucleinopathies underscores iron accumulation in substantia nigra and other brain regions as a hallmark pathological feature. Postmortem and neuroimaging studies corroborate local iron deposition contributing to reactive oxygen species generation and neuronal vulnerability. Peripheral blood markers such as ferritin provide accessible surrogates reflecting systemic iron burden and inflammatory milieu.
Meta-analyses in PD cohorts suggest elevated serum ferritin associates with worse motor function and disease progression velocity, although data heterogeneity and confounders like comorbid systemic inflammation exist. The Yin et al. study elucidates this dysregulation at the prodromal iRBD stage, informing early pathophysiological changes preceding overt neurodegeneration.
Expert Commentary
The robust association between elevated serum ferritin and phenoconversion risk in iRBD advances our understanding of prodromal pathophysiology. Ferritin not only serves as a biomarker for disease severity but potentially contributes mechanistically through oxidative stress pathways.
The dual elevation of pro- and anti-inflammatory cytokines alongside ferritin suggests a complex immune regulatory environment in iRBD. IL-10 elevation may reflect a compensatory anti-inflammatory response attempting to mitigate neuroinflammation, while TNF-α elevation indicates active inflammation fostering neurodegenerative cascades.
Clinically, serum ferritin measurement is inexpensive, widely available, and may be integrated into screening algorithms for iRBD patients to stratify risk and tailor monitoring frequency. However, care must be taken to exclude confounding from systemic infections, liver disease, or malignancies which also alter ferritin levels.
Mechanistically, future research integrating neuroimaging iron quantification (e.g., susceptibility-weighted MRI), cerebrospinal fluid biomarkers, and longitudinal inflammation profiling could elucidate causality and temporal dynamics.
Limitations include moderate sample size and single-center design. Validation in multiethnic cohorts and with extended follow-up is necessary. Interventional studies addressing iron chelation or anti-inflammatory approaches may extend the translational impact.
Conclusion
Emerging evidence highlights peripheral iron metabolism dysregulation and concomitant inflammation as integral components in the prodromal phase of α-synucleinopathies, exemplified by iRBD. Elevated serum ferritin independently predicts phenoconversion, correlates with symptom severity, and is linked to systemic inflammatory activation.
This knowledge enhances predictive models and suggests that targeting iron-inflammation crosstalk could mitigate progression. Future directions should prioritize longitudinal mechanistic investigations and therapeutic trials addressing iron homeostasis and neuroinflammation to forestall neurodegeneration in iRBD.
References
- Yin W, Zhang X, Ren J, et al. Serum Ferritin and Inflammation in Isolated REM Sleep Behavior Disorder: A Longitudinal Study. Neurology. 2026;107(4):e218173. doi:10.1212/WNL.0000000000018173. PMID: 42551002.
- Postuma RB, Iranzo A, Hu M, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study. Brain. 2019;142(3):744-759. doi:10.1093/brain/awy318. PMID: 30535131.
- Ward RJ, Zucca FA, Duyn JH, et al. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13(10):1045-1060. doi:10.1016/S1474-4422(14)70117-6. PMID: 25215181.
- Faucheux BA, Martin ME, Beaumont C, et al. Lack of correlation between serum ferritin and brain iron in Parkinson’s disease. Mov Disord. 2004;19(5):540-544. doi:10.1002/mds.10792. PMID: 15110798.
- Jellinger KA. Neuropathology of sporadic Parkinson’s disease: evaluation and changes of concepts. Mov Disord. 2012;27(1):8-30. doi:10.1002/mds.24962. PMID: 22271276.
