Abstract
BackgroundDopaminergic neuronal loss begins years before motor symptoms appear in Parkinson disease (PD). Thus, reliable biomarkers for early diagnosis and prognosis of PD are an essential pre-requisite to develop disease modifying therapies. Inflammation-derived oxidative stress is postulated to contribute to nigrostriatal degeneration. We evaluated the role of selected serum immune mediators (IFNγ, TNFα, IL-10, and NOx) in PD progression and estimated their usefulness in preclinical diagnosis.MethodsThis case-control study recruited 72 PD patients with varying disease durations (< 1-year, n = 12 patients; 1–3 years, n = 30; > 3 years, n = 30) and 56 age- and gender-matched controls (26 with other neurological disorders as disease controls, and 30 healthy controls). Serum cytokine levels and NOx quantified using Sandwich Enzyme Linked Immunosorbent Assay kits, and the Griess test, respectively, were evaluated for diagnostic accuracy of optimal marker combinations by the CombiROC method. PD patients were clinically evaluated for motor and non-motor symptoms, and staged based on Hoehn and Yahr (H-Y) scale.ResultsA significant increase in serum IFNγ and IL-10 was observed in PD compared to healthy controls (p < 0.001). The Th1: Th2 (IFNγ: IL-10) cytokine ratio was higher in PD of 3–12 years compared with PD < 1 year (p < 0.001). Highest levels of NOx manifested during early PD (1–3 years) through a subsequent decline with disease duration. TNFα level was highest at PD onset. A low serum NOx level was associated with cognitive impairment (p = 0.002). The potential of using multi-biomarker panel, IFNγ, IL-10 and TNFα, for detection of PD onset was evident (sensitivity [SE] = 83.3%, specificity [SP] =80.4%, area under curve [AUC] = 0.868), while for early and late PD the multi-biomarker signature of IFNγ, IL-10 and NOx appeared to be more promising (SE = 93.3%, SP = 87.5%, AUC = 0.924).ConclusionA Th1 cytokine-biased immune response predominates with PD progression. Both IFNγ and IL-10 are involved in disease severity. However, TNFα-mediated neurotoxicity appears to occur in early PD.
Highlights
Dopaminergic neuronal loss begins years before motor symptoms appear in Parkinson disease (PD)
A Th1 cytokine-biased immune response predominates with PD progression
Participant characteristics A total of 72 patients with idiopathic PD of varying disease durations, 30 normal healthy controls and 26 with other neurological disorders were recruited for the study
Summary
Dopaminergic neuronal loss begins years before motor symptoms appear in Parkinson disease (PD). A broad spectrum of neurodegenerative diseases are associated with chronic inflammation in the central nervous system (CNS) including Parkinson disease (PD) [1, 2] This inflammation-derived oxidative stress is postulated to be a contributor in degeneration of the nigrostriatal pathway hastening PD progression [3]. Given that PD is a neurodegenerative disease, it is imperative that disease modifying strategies are administered at an early stage of the disease if it is to have any impact on the disease course [6] In this context, it is crucial to identify clinically useful reliable biomarkers that will be able to identify PD long before the manifestations of motor symptoms, which is a neuropathologically advanced stage at which PD is diagnosed currently
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