Challenges in Parkinsonʹs disease: restoration of the nigrostriatal dopamine system is not enough

Summary Levodopa remains the most effective treatment for Parkinsonʹs disease (PD). However, the drug is complicated by a wide range of adverse effects, most notably motor fluctuations and dyskinesias. Long-acting dopamine agonists are associated with a reduced incidence of these complications and modern surgical approaches and pharmacological methods of providing more continuous dopaminergic stimulation have a substantial ameliorative effect on these problems. Despite these advances, disease progression remains unaffected. For this reason there has been much enthusiasm for cellular therapies designed to replace degenerating nigrostriatal dopaminergic neurons. However, recent fetal transplant trials have failed to show expected benefit and have been complicated by “off medication dyskinesias”. Even if successful, such treatment may be predestined to provide no better outcome than available treatments given current medical and surgical experience that emphasises the increasingly critical role of “non-dopaminergic” symptoms to quality of life in late-stage PD. Knowledge of the widespread, multisystem nature of the neurodegeneration that accounts for these problems suggests that restoration of the nigrostriatal dopamine system should not be the ultimate goal of future research.