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.

中文翻译：

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帕金森病的终生演变如何影响临床试验设计：患者与临床医生的共同观点

帕金森病（PD）有一个漫长的、异质的诊断前阶段，在此期间病理学在不知不觉中累积。越来越多的证据表明，生命早期的环境和生活方式因素会导致疾病风险和进展。由于对诊断前阶段的广泛研究，第一个 PD 预防试验正在设计中。然而，疾病在整个生命过程中的高度异质性演变尚未得到充分考虑。这可能会阻碍生物疾病定义出现时临床试验的成功。在一个跨学科的患者-临床医生研究小组中，我们讨论了一种结合 PD 终生演变的方法如何通过影响人群、目标和结果选择来有益于疾病修饰试验的设计。我们认为，暴露于风险和保护因素的时间点在 PD 亚型中起着关键作用，影响人群选择。此外，在生物学疾病定义的帮助下，不同疾病机制的最新发展可能会影响最佳治疗目标。最后，使用这种终生方法的多模式生物标志物组合可能作为更个性化试验的进展标志物最敏感。我们认为，在临床试验的设计中应考虑帕金森病的终生演变，并且此类举措可以从更多的患者与临床医生合作中受益。