Abstract
Pathological and neuroimaging studies have shown that in Parkinson's disease (PD) there is a โsubclinicalโ or โpremotorโ period during which dopaminergic neurons in the substantia nigra (SN) degenerate but typical motor symptoms have not yet developed. Postโmortem studies based on nigral cell counts and evaluating dopamine levels in the striata, and imaging studies assessing the nigrostriatal pathway in vivo, have estimated that this time period could last 3 to 6 years. In addition, emerging evidence indicates that the neuropathological process of PD does not start in the SN but more likely elsewhere in the nervous system: in the lower brainstem and the olfactory bulb, or even more distant from the SN, such as in the peripheral autonomic nervous system. Patients with PD frequently can present nonโmotor symptoms, such as hyposmia or constipation, years before the development of classical motor signs. The physiopathology of these โpremotorโ symptoms, though still unclear, is currently thought to be related to early involvement by the pathological process underlying PD of nonโdopaminergic lower brainstem structures or autonomic plexuses. However, the answer to the question โwhen does PD startโ remains uncertain. Here, we review clinical, pathological, and neuroimaging data related to the onset of the pathological process of PD, and propose that its onset is nonโmotor and that nonโmotor symptoms could begin in many instances 10 and 20 years before onset of motor symptoms. The variable course of the disorder once the motor symptoms develop, suggests that the start and progression of premotor PD is also highly variable andgiven the heterogeneous nature of PD, may differ depending on the cause/s of the syndrome. When and where the neuropathological process develops in PD remains uncertain. ยฉ 2009 Movement Disorder Society