ABSTRACT
INTRODUCTION Parkinson’s disease (PD) is the second most common neurodegenerative condition after Alzheimer’s disease, affecting at least one million people in the United States and four to six million people worldwide (1). The economic cost is estimated at $23 billion a year in the United States alone and, with the aging population, that cost is estimated to increase to $50 billion a year by 2040. Since its initial description by James Parkinson in 1817, the cardinal motor features of rest tremor, rigidity, bradykinesia, and postural instability have characterized PD. This understanding was reinforced by the seminal work of Carlsson who suggested that dopamine depletion played a crucial role in the development of motor symptoms (2). By the 1960s Ehringer and Hornykiewicz (3) found that patients who had died of PD had marked depletion of dopamine in the substantia nigra and shortly thereafter Cotzias (4) demonstrated the profound benefi cial effect of levodopa on motor symptoms. With time however, it became clear that dopamine replacement therapy was not a panacea. Patients developed motor complications and dyskinesia. More importantly, nonmotor symptoms, such as dementia, apathy, depression, and sleep disturbances emerged and did not respond to dopaminergic therapies (5,6). Indeed, as the disease progresses, non-levodopa responsive nonmotor symptoms can be the most debilitating feature for both patients and caregivers (7).
