When does Parkinson's disease begin? From prodromal disease to motor signs

Cardinal motor features of Parkinson's disease (PD) appear when about half of the nigral dopamine neurons have disappeared. Based on extrapolations from post-mortem and imaging studies, the delay between the onset of dopamine denervation and the appearance of motor signs ranges from 5 to 20years. According to Braak and co-workers, motor symptoms only appear at stage III of PD, while the neurodegenerative process begins earlier in the olfactory bulb and lower brain stem. In addition to the cardinal motor features, non-motor signs are increasingly being recognized in PD. Some of them, mainly olfactory disturbances, rapid-eye-movement sleep behaviour disorder and autonomic dysfunction, are already present in the early disease stages and may precede the onset of motor signs by up to four decades. These non-motor signs are related to widespread extranigral and even extracerebral degeneration, and have been considered risk factors for many years. Indeed, recent evidence suggests that they may be prodromal manifestations of PD. From the perspective of future disease-modifying or neuroprotective treatments, combining prodromal non-motor signs and paraclinical investigations may help to further develop reliable tools for early diagnosis of PD before the onset of its cardinal motor features.