Hepatitis C Virus Infection: A Risk Factor for Parkinson's Disease

W. Y.-Y. Wu; K.-H. Kang; S. L.-S. Chen; S. Y.-H. Chiu; A. M.-F. Yen; J. C.-Y. Fann; C.-W. Su; H.-C. Liu; C.-Z. Lee; W.-M. Fu; H.-H. Chen; H.-H. Liou

Disclosures

J Viral Hepat. 2015;22(10):784-791. 

In This Article

Abstract and Introduction

Abstract

Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory biomarkers. We analysed data from a community-based integrated screening programme based on a total of 62 276 subjects. We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron–glia coculture system in rats. The cytokine/chemokine array was performed to measure the differences of amounts of cytokines released from midbrain in the presence and absence of HCV. The crude odds ratios (ORs) for having PD were 0.62 [95% confidence interval (CI), 0.48–0.81] and 1.91 (95% CI, 1.48–2.47) for hepatitis B virus (HBV) and HCV. After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07–1.80), but not significantly different between HBV and PD. The HCV induced 60% dopaminergic neuron death in the midbrain neuron–glia coculture system in rats, similar to that of 1-methyl-4-phenylpyridinium (MPP+) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD. In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP+.

Introduction

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein aggregates in Lewy bodies.[1] Although the cause of PD remains unclear, it has been shown that numerous viruses are associated with both acute and chronic parkinsonism including influenza, Coxsackie, Japanese encephalitis (JE), western equine encephalitis, herpes and acquired immunodeficiency disorder (HIV). These viruses are neurotropic and they may induce a number of encephalopathies that lead to parkinsonism.[2] Hepatitis C virus (HCV) belongs to the flaviviridae family, which includes well-known neurotropic viruses, such as JE, yellow fever, dengue and tick-borne encephalitis viruses.[3] Recent studies suggest that HCV may invade the central nervous system (CNS). Such neuroinvasive harm shows sign of evidence that patients with mild chronic HCV infection had elevated choline/creatine ratios, a biomarker indicating inflammatory and infective conditions, in the basal ganglia and white matter.[4] Moreover, a viral replicative intermediate of HCV RNA has been found in autopsy brain tissue and activation of macrophages/microglial cells has been found in HCV-positive patients.[5,6] In addition, alteration of striatal dopaminergic neurotransmission has been reported in HCV-infected patients.[7] The evidence that HCV can replicate in the CNS suggests a possible link between PD and HCV.

The association between HCV infection and the pathogenesis of PD is also supported by both HCV infection and PD having in common the overexpression of inflammatory biomarkers that are related to rising concentrations of cytokines in neuronal generation processes, such as abnormal protein handling, oxidative stress, mitochondrial dysfunction, excitotoxicity and apoptotic processes.[6]

Despite this speculation, it is rare and difficult to have available information on HCV infection and PD simultaneously in a population- and community-based epidemiological study to assess this hypothesis. Thus, at population and epidemiology level, we attempted to assess whether HCV infection was associated with PD using data from the Keelung community-based integrated screening (KCIS) programme with information on HCV infection, diagnosis of PD and other confounding factors available.[8] At the molecular level, we investigated the dopaminergic toxicity of HCV and compared that of 1-methyl-4-phenylpyridinium (MPP+), the pathognomonic chemical in experimental parkinsonism study. Furthermore, the differences in the relative amounts of cytokines released from midbrain in the presence and absence of virus were measured by cytokine/chemokine array to investigate the pathogenesis of PD.

processing....