How Lifetime Evolution of Parkinson's Disease Could Shape Clinical Trial Design: A Shared Patient-Clinician Viewpoint

Abstract

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.

Keywords: Parkinson’s disease; disease-modifying treatment; lifetime research; patient–clinician collaboration.

Figure 1

Conceptual model representing the accumulation of Parkinson’s disease (PD) pathology through one (hypothetical) lifetime with diagnosis at age 66, and the putative effect of disease-modifying intervention. 1: Classic development of manifest PD where, early in life, some individuals are exposed to triggers and facilitators of PD pathology. Solid arrow: current age range of de novo study inclusion and mean participation in studies in manifest PD [17,18], where ‘the horse has already left the barn’. 2: Slowing of PD development due to protective factors such as disease-modifying therapies or lifestyle habits. It also represents insufficient presence of facilitators for the development of manifest PD from prodromal PD (gross age ranges depicted for visualization purposes). 3: Individuals who have been exposed to triggers but do not develop sufficient pathology for PD symptoms. Dotted arrow: early intervention opportunities as identified by individual PD risk profile (genetic risk, exposome, positive α-synuclein seeding assay, etc.).

Figure 2

Example of identification of PD subgroups in trial populations based on specific biomarkers and their relationship to specific pathophysiological mechanisms. (a) heterogenous PD population. (b) subgroups based on specific biomarkers. (c) subgroup differences in functional and structural connectivity within the metabolic network core, so called Parkinson’s disease-related patterns (PDRPs). (d) subgroup differences in motor function based on Short Parkinson’s Evaluation Scale/Scales for Outcomes in Parkinson’s Disease (SPES/SCOPA). (e) subgroup differences in cognitive function based on Mini-Mental State Examination (MMSE). GBA: glucocerebrosidase. LRRK2: leucine-rich repeat kinase 2. iPD: idiopathic PD.