The natural history of Parkinson's disease.

Although Parkinson's disease (PD) is the only chronic neurodegenerative disorder for which there are effective symptomatic therapies no treatment has yet been identified that would significantly slow its natural progression. Studies into the natural history of Parkinson's disease have been complicated by issues of diagnostic accuracy, heterogeneity of different forms of the disease as well as confounding effects of age related comorbidities. Only recently results from placebo-controlled clinical trials have helped to define the rates of progression of motor dysfunction as assessed by the UPDRS in early PD. Studies in treated patients suggest that there may be different rates of progression in different phases of the disease with faster decline in earlier versus later stages. Measuring progression of motor symptoms, however, alone is insufficient to describe the natural history of PD and may also be inadequate to define clinically meaningful disease modification in intervention trials. Progression of global disability as captured in the Hoehn and Yahr scale is important to consider and progression to stage III with beginning postural impairment defines a major milestone in the natural history of this illness. In addition, non-motor symptoms have major impact on the natural history of PD. Dementia, sleep-wake cycle dysregulation and autonomic failure were present in 50-80% of patients in one recent 15 year-follow up study. Dementia and psychosis are also major risk factors for nursing home placement in PD. A prerequisite for effective interventions that would modify disease progression in Parkinson's disease is the identification of the earliest preclinical stages of illness. This is now become a realistic possibility with screening tests of olfactory function and subsequent functional imaging. Subjects at risk for Parkinson's disease should be the future focus of neuroprotective trials.