Loss of substantia nigra pars compacta (SNc) dopaminergic neurons is considered to be the most important neuropathologic hallmark of Parkinson disease (PD). Focus on the nigrostriatal dopaminergic system is justified by the prominent motor manifestations for which patients seek treatment and the remarkable success of dopamine replacement therapy. However, it has become increasingly apparent that the neuropathologic changes of PD extend well beyond the nigrostriatal system (Figure). Even components of the early core motor symptoms may not be exclusively related to nigrostriatal dopamine deficiency. This is particularly the case for tremor for which animal models and clinical, pharmacologic, positron emission tomography, and postmortem studies support an important role for extranigral mechanisms (Table 1).1Most of the disability brought on by advancing PD relates to the emergence of symptoms that respond poorly, if at all, to levodopa or modern surgical therapies; these disabilities include “on”-medication axial motor features such as gait freezing, postural instability with falls, dysarthria and dysphagia, and a broad spectrum of nonmotor symptoms. Nonmotor symptoms comprise a variety of neuropsychiatric, autonomic, sensory, and sleep disorders. Although some of these symptoms, such as dementia and psychosis, typically appear late in the course of the disease, other nonmotor symptoms may occur early in the disease, even before the onset of motor problems, and many continue to be common across all stages of PD. Although the anatomic, pathologic, and biochemical substrates for much of the PD symptom complex are yet to be fully characterized, significant progress has been made. Pathologic changes occur in widespread regions of the central and peripheral nervous systems, and it is recognized that many different neurotransmitter systems (eg, noradrenergic, serotonergic, and cholinergic) in addition to dopamine are deranged as part of the multisystem neurodegeneration that constitutes PD. Increasing evidence suggests that in most cases the first neurons affected in PD are nondopaminergic, and the SNc may become involved only after the disease is well established in other regions of the nervous system.2Indeed, α-synuclein–containing Lewy bodies (LBs), the histologic hallmark of PD, were first described almost a century ago in the nondopaminergic neurons of the dorsal motor nucleus of the vagal nerve, nucleus basalis of Meynert, and hypothalamus. On the other hand, abnormalities in extranigral dopaminergic systems (mesolimbic, mesocortical, and thalamic) also likely contribute to the PD symptom complex.