The clinical progression of Parkinson's disease.

Parkinson's disease (PD) is known as a chronic neurodegenerative disorder with a relentlessly progressive course of illness. Although in recent decades there have been many advances in symptomatic therapy, there is still no established therapy that will halt or slow progression in a clinically meaningful way. So far, disease-modification trials have focused on indices of progression of cardinal motor features such as bradykinesia, rigidity and tremor as captured by the Unified Parkinson's Disease Rating Scale, and the emerging need for effective symptomatic dopaminergic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation, leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites inevitably leads to poorly L-dopa-responsive motor symptoms such as postural instability, freezing and falls, or non-motor symptoms. Furthermore, treatment-induced motor complications also contribute to PD disability. Progression of PD is multidimensional with superimposed age-related co-morbidities. Hence there is no consensus on how to best implement more clinically meaningful end-points for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers identifying preclinical stages of illness and describing disease progression--thus faithfully reflecting early and advancing neurodegeneration--that could be used in short-term clinical trials testing putative disease-modifying agents. Copyright 2009 Elsevier Ltd. All rights reserved.