Prodromal PD: A new nosological entity.

Recent years have brought a rapid growth in knowledge of the prodromal phase of Parkinson's disease (PD). It is now clear that the clinical phase of PD is preceded by a phase of progressing neurodegeneration lasting many years. This involves not only central nervous system structures outside the substantia nigra and neurotransmitter systems other than the dopaminergic system, but also the peripheral nervous systems. Different ways of alpha-synuclein spreading are presumed, corresponding to typical prodromal non-motor symptoms like constipation, REM sleep behavior disorder (RBD) and hyposmia. Moreover, many risk and prodromal markers have been identified and combined in the prodromal research criteria, which can be used to calculate an individual's probability of being in the prodromal phase of PD. Apart from specific genetic risk markers, including most importantly GBA- and LRRK2 mutations, RBD is currently the most important prodromal marker, predicting PD with a very high likelihood. This makes individuals with RBD a promising cohort for future clinical trials to detect and treat PD in its prodromal phase. New markers, especially those derived from tissue biopsies, quantitative motor assessment and imaging, appear very promising; these are paving the way for a better understanding of the prodromal phase and its potential clinicopathological subtypes, and a more precise probability calculation.