The progression of Parkinson disease: a hypothesis

Recent neuropathologic studies suggest that Parkinson disease (PD) does not begin in the substantia nigra compacta (SNc) but only involves this region later in the course of the disease. It is proposed that once the SNc is affected by the original pathobiological process (for example, protein aggregation), additional processes more specific to dopaminergic neurons are triggered (including sources of oxidative stress such as increased dopamine turnover, reduced levels of reduced glutathione, increased iron, and the presence of neuromelanin, as well as altered calcium homeostasis and excitotoxicity). This results in an acceleration of cell loss in the SNc, causing nigrostriatal degeneration to both reach a threshold for symptoms in advance of earlier affected brain areas and progress more rapidly than other aspects of the disease. Neuroprotective therapy directed solely at more general biologic processes may not have sufficient effects on this accelerated degeneration in the SNc, while neuroprotective therapy designed exclusively to slow the progression of dopaminergic cell loss will not alter the progression of the nondopaminergic symptoms that contribute the greatest disability in the later stages of the disease. Effective disease-modifying therapy may require a cocktail combining treatments designed to address the basic mechanisms of the neurodegeneration and the additional biologic processes specific to the dopaminergic SNc. This hypothesis has implications for the development of disease-modifying therapy and the interpretation of endpoints of clinical trials evaluating the efficacy of such treatments.