Our collective thinking about
Parkinson disease (PD) has been heavily influenced by the dramatic response to
dopamine replacement
therapy. For progress to continue, however, we need to take a broad view of this disorder, which includes recognition of the following. First, substantial evidence now indicates that
dopamine oxidation is unlikely to substantially contribute to the pathogenesis of PD. Second,
levodopa therapy is not associated with neurotoxicity. Third, the first neurons affected in PD are nondopaminergic; the substantia nigra and other dopaminergic nuclei are affected only later in the course. Thus, PD is much more than degeneration of the dopaminergic nigrostriatal system. Fourth, in the current era, most of the disability of advancing PD is from involvement of nondopaminergic systems, including
levodopa-refractory motor symptoms,
dementia, and
dysautonomia. Motor complications associated with
levodopa therapy can be problematic, but they can be controlled in most, using available medications and
deep brain stimulation surgery. We have reached the point of diminishing therapeutic returns with drugs acting on
dopamine systems; more dopaminergic medications will provide only modest incremental benefit over current
therapies. Finally, the benefits from
transplantation surgeries aimed at restoring dopaminergic neurotransmission will be limited because later-stage PD disability comes from nondopaminergic substrates. Scale.