Modifying effect of ceruloplasmin polymorphism on iron chelation response in Parkinson's disease

Abstract

Introduction: In Parkinson’s disease (PD), excess iron is detected primarily in the substantia nigra (SN), where dopaminergic neurons are exposed to high levels of reactive oxygen species. Excess labile iron can enhance neuronal death by Fenton reaction. By oxidation of iron, ceruloplasmin allows iron transportation between blood and cells. Ceruloplasmin metabolism disturbances may increase brain iron overload. Our aim was to evaluate the interaction between iron chelation response on clinical, biological and MRI parameters and the ferroxidase activity in relation with the ceruloplasmin polymorphism D544E.<br /><br />Methods: A pilot, double blind, placebo-controlled randomized clinical trial with a 6-month delayed-start paradigm, was set in 40 patients on stabilized dopamine regimens with deferiprone. Effects of deferiprone were analyzed according to the ceruloplasmine genotypes, on motor UPDRS, MRI R2* sequences (indirect assessment of iron overload) and blood iron metabolism.<br /><br />Results: Early-start patients (n=19) compared to delayed start patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both SN iron deposits (R2* MRI) and motor UPDRS . The AT group (n=5) had a greater clinical improvement, an greater increase in ceruloplasmin levels and a greater reduction of R2* value as compared with AA group (n=32).<br /><br />Conclusions: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a therapeutic modality for all PD patients but with a higher benefit in patients carrying the AT polymorphism. Lower ceruloplasmin activity may be at higher risk of iron metabolism dysfunction and may require stronger iron chelation.