Abstract：
Therapies that prevent the occurrence of Parkinson disease (PD) (primary prevention) or mitigate the progression of symptoms in those with early disease (secondary prevention) are a critical unmet need in disease management. Despite great promise, PD prevention trials have not yet demonstrated success. Initiation of treatment too late in the disease course and the heterogeneity of disease are obstacles that may have contributed to the failure. Genetically stratified groups offer many advantages to primary and secondary prevention trials. In addition to their ease of identification, they decrease disease heterogeneity on several levels. Particularly, they comprise a phenotypically and pathologically enriched group with defined clinical features, pathogenic mechanisms and associated proteins that may serve as specific trial endpoints, therapeutic targets and biomarkers for disease state, and pharmacodynamic and pharmacokinetic status. However, challenges arise from genetic variant heterogeneity, from reduced penetrance whereby many carriers will not develop PD, and in recruiting a population that will meet the desired outcome in the proposed study duration. In this review, we discussed the opportunities afforded by the enrollment of genetically stratified cohorts (i.e., leucine-rich repeat kinase 2 and glucocerebrosidase 1) into prevention trials with a primary focus on primary prevention trials. We also outlined challenges surrounding the enrollment of these cohorts and offered suggestions to leverage their many advantages.
摘要：
预防帕金森病（PD）的发生（一级预防）或减轻早期疾病患者症状进展（二级预防）的疗法是疾病管理中尚未满足的关键需求。尽管有很大的希望，PD预防试验尚未证明成功。在疾病过程中太晚开始治疗和疾病的异质性是可能导致失败的障碍。遗传分层组为一级和二级预防试验提供了许多优势。除了易于识别外，它们在几个层面上减少了疾病的异质性。特别是,它们包括具有明确临床特征的表型和病理富集组，致病机制和可能作为特定试验终点的相关蛋白，疾病状态的治疗靶标和生物标志物，以及药效学和药代动力学状态。然而,挑战来自遗传变异异质性，由于降低了外显率，许多携带者不会发展PD，并招募在建议的研究持续时间内符合预期结果的人群。在这次审查中,我们讨论了遗传分层队列的登记所提供的机会(即，富含亮氨酸的重复激酶2和葡糖脑苷脂酶1）进入预防试验，主要侧重于一级预防试验。我们还概述了围绕这些队列注册的挑战，并提出了利用其许多优势的建议。
