Pathogenesis of motor response complications in Parkinson’s disease: “Mere conjectural suggestions” and beyond

In his 1817 monograph, James Parkinson expressed the wish that his essay would excite others to “extend their researches” to this disease so that they might “point out the most appropriate means of relieving a tedious and most distressing malady.”1 It was not until 1967 that his wish was granted, but the advent of levodopa was well worth the wait.2 Levodopa still stands out among other therapies in neurology as a rational neurotransmitter replacement strategy that confers great benefit to its target population. Unfortunately, Parkinson did not have the foresight to wish that “the relief of this distressing malady” should last indefinitely. Soon after the introduction of levodopa, it became clear that its chronic use is associated with motor Ÿuctuations and dyskinesia that eventually occur in the majority of patients with advanced Parkinson’s disease (PD) and can be major causes of disability in their own right.2,3 Thus, paraphrasing Parkinson’s words, we are now confronted with the remaining challenge “to point out appropriate means to prevent or relieve the long-term complications of levodopa treatment.”.