LAUSR

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as bradykinesia, tremor, and gait and postural abnormalities as well as neuropsychiatric and other nonmotor symptoms. It is more common in older adults and increases in prevalence with age, although it can also affect younger individuals. Worldwide, approximately 7.5 million people are estimated to be living with PD, and by 2040 this number is expected to double over the next 2 decades. The pathophysiological mechanisms behind PD are unclear; however, a variety of immunological, inflammatory, toxic, and potentially infectious etiologies have been considered in the pathogenesis of the disease. Multiple individual characteristics have been identified that can increase the risk of developing PD, but only a few of the risk factors identified to date might actually be treatable. One potential association that has generated recent interest is that between hepatitis C virus (HCV) infection and the risk of developing PD.1 The infection is a major cause of hepatic disease worldwide and is highly associated with the later occurrence of hepatocellular carcinoma, liver failure, and cirrhosis. It also increases the risk of developing other systemic medical complications.2 Experiments have shown that HCV infection can induce dopaminergic neuron death.3 Abnormal markers of neuroinflammation, brain viral replicative RNA, and impairment of striatal dopaminergic neurotransmission have all been reported in patients with HCV infection.4-6 Several epidemiologic studies have also suggested a possible association between HCV infection and PD.1,7 One of the main questions raised by observational studies has been the possible role of antiviral therapy in delaying or preventing the later development of PD. In this issue of JAMA Neurology, Lin and colleagues8 report on a retrospective cohort study they conducted using the Taiwan National Health Insurance Research Database to assess the risk of developing PD in patients with HCV infection treated with antiviral therapy. The authors identified 242 568 patients with HCV infection using International Classification of Diseases, Ninth Revision, Clinical Modification codes from January 2003 to December 2013. Patients with an established history of severe liver disease, stroke, dementia, or PD were excluded. A total of 188 152 individuals were included in the final analysis and divided into 2 groups: those who received interferon alfa-2b and ribavirin, and those who did not receive antiviral treatment. After correcting for multiple variables, the main outcome of the study was the development of PD. Lin and colleagues8 performed propensity score matching with covariate adjustment to match the characteristics of patients between groups. Each treated patient was paired with a corresponding untreated patient to minimize treatment selection bias. Faced with the wide ranges and variability of age, demographics, and comorbidities, the authors decided to use propensity score matching to balance the covariates between the exposed and unexposed groups. The authors found that although no early differences were noted, a statistically significant difference was found between the 2 groups in the fifth year. There was a slower rate of developing PD in patients treated with antiviral therapy. Lin and colleagues8 concluded that HCV infection was a risk factor for PD and that interferonbased antiviral therapy could lower that risk. They noted that the incidence of PD was reduced but was not eliminated by antiviral therapy, acknowledging that other factors also were present in the mechanisms of a complex disease such as PD. In addition, the authors did not observe transient parkinsonism in patients treated with interferon-based antiviral therapy as previously reported in small observational studies.9 The results of this study are relevant to both the fields of neurology and hepatology, as they reveal a potentially treatable hepatological risk factor for the development of PD. The findings also add to the evolving knowledge about the association between immunological and infectious factors in PD and related disorders. Furthermore, they suggest mechanisms that may be responsible for this association, including neuroinflammation and clearance of HCV infection. Although pathogenic mechanisms between HCV infection and PD remain unconfirmed, it is possible that HCV infection enters the brain through the microvasculature and then induces microglial and macrophages inflammatory changes, with damage associated with the release of neurotoxins such as nitric oxide and proinflammatory cytokines, including tumor necrosis factor, IL-1, and IL-6.10 Other potential mechanisms include immune cross-reactivity between HCV peptides and brain tissue antigens that leads to neurodegeneration.11 Although Lin and colleagues8 estimated a high diagnostic accuracy for PD, the diagnosis was based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and medication records but lacked clinical, neuroimaging, or pathological confirmation, which is a limitation of the study. The diagnosis of PD in early stages can be challenging as other related conditions can mimic PD, including cirrhosis-related parkinsonism. Moreover, using record-linkage systems excludes patients who did not seek medical advice or those who were misdiagnosed by symptoms alone, which may Related article Opinion