Pathogenesis and preclinical course of Parkinson's disease

Idiopathic parkinsonism (IP) is defined by its classic symptomology, its responsiveness to therapies which elevate dopamine levels, and by the failure to identify a specific etiological factor. The progressive and irreversible degeneration of dopaminergic neurons projecting from the substantia nigra pars compacta (SNc) to the striatum and the presence of SNc Lewy bodies are regarded as the essential pathological bases of IP, but neither the initiator(s) nor the nature of the degeneration have been determined, nor its relationship with degenerative changes in other parts of the IP brain. This paper discusses the various hypotheses that have been proposed to explain these phenomena, arguing that IP be regarded as a multisystem disorder, both at the level of individual neurons and at the whole brain level. It is probable that IP is the result of a multifactorial process, and that a cascade of interacting and overlapping biochemical mechanisms determine the course of the disease.