Increased Plasma Heme Oxygenase-1 Levels in Patients With Early-Stage Parkinson’s Disease

Abstract

<b>Introduction</b>: Heme oxygenase-1 (HO-1) is a 32 kDa stress-response protein implicated in the pathogenesis of Parkinson's disease (PD). Biliverdin is derived from heme through a reaction mediated by HO-1 and protects cells from oxidative stress. However, iron and carbon monoxide produced by the catabolism of HO-1 exert detrimental effects on patients with PD. The purpose of this study was to determine whether plasma HO-1 levels represent a biomarker of PD and to further explore the underlying mechanism of increased HO-1 levels by applying voxel-based morphometry (VBM).<b>Methods</b>: We measured plasma HO-1 levels using an enzyme-linked immunosorbent assay (ELISA) in 156 subjects, including 81 patients with early- and advanced-stage PD and 75 subjects without PD. The analyses were adjusted to control for confounders such as age, sex, and medication. We analyzed T1-weighted magnetic resonance imaging (MRI) data from 74 patients with PD using VBM to elucidate the association between altered brain volumes and HO-1 levels. Then, we compared performance on MMSE sub-items between PD patients with low and high levels of HO-1 using Mann-Whitney <i>U</i> tests.<b>Results</b>: Plasma HO-1 levels were significantly elevated in PD patients, predominantly those with early-stage PD, compared with controls (<i>p</i> < 0.05). The optimal cutoff value for patients with early PD was 2.245 ng/ml HO-1 [area under the curve (AUC) = 0.654]. Plasma HO-1 levels were unaffected by sex, age, and medications (<i>p</i> > 0.05). The right hippocampal volume was decreased in the subset of PD patients with high HO-1 levels (<i>p</i> < 0.05). A weak correlation was observed between right hippocampal volume and plasma HO-1 levels (<i>r</i> = -0.273, <i>p</i> = 0.018). There was no difference in total MMSE scores between the low- and high-HO-1 groups (<i>p</i> > 0.05), but the high-HO-1 group had higher language scores than the low-HO-1 group (<i>p</i> < 0.05).<b>Conclusions</b>: Plasma HO-1 levels may be a promising biomarker of early PD. Moreover, a high plasma concentration of the HO-1 protein is associated with a reduction in right hippocampal volume.