Sirwan K. L. Darweesh

Parkinson’s disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention trials of PD are being designed. However, the highly heterogenous evolution of the disease across the life course is not yet sufficiently taken into account. This could hamper clinical trial success in the advent of biological disease definitions. In an interdisciplinary patient–clinician study group, we discussed how an approach that incorporates the lifetime evolution of PD may benefit the design of disease-modifying trials by impacting population, target and outcome selection. We argue that the timepoint of exposure to risk and protective factors plays a critical role in PD subtypes, influencing population selection. In addition, recent developments in differential disease mechanisms, aided by biological disease definitions, could impact optimal treatment targets. Finally, multimodal biomarker panels using this lifetime approach will likely be most sensitive as progression markers for more personalized trials. We believe that the lifetime evolution of PD should be considered in the design of clinical trials, and that such initiatives could benefit from more patient–clinician partnerships.