PDF(Pubmed)
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.
摘要：
帕金森病(PD)有很长一段时间,异质，预诊断阶段，在这个过程中，病理学阴险地积累。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。由于对这一诊断前阶段的广泛研究，PD的第一批预防试验正在设计中。然而,尚未充分考虑到该疾病在整个生命过程中的高度异质性演变。这可能会阻碍生物学疾病定义的出现的临床试验成功。在一个跨学科的患者-临床医生研究小组中，我们讨论了结合PD的终生进化的方法如何通过影响人群而有益于疾病改善试验的设计，目标和结果选择。我们认为，暴露于风险和保护因素的时间点在PD亚型中起关键作用，影响人口选择。此外,鉴别疾病机制的最新发展，在生物疾病定义的帮助下，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小组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该考虑PD的寿命演变，并且这些举措可以受益于更多的患者-临床医生伙伴关系。
