The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and applied biologic and clinical data-informed definitions for the NSD-ISS across the disease continuum. Individuals enrolled as Parkinson’s disease, Prodromal, or Healthy Controls were defined and staged based on biological, clinical, and functional anchors at baseline. Across the three studies 1741 participants had SAA data and of these 1030 (59%) were S+ consistent with NSD. Among sporadic PD, 683/736 (93%) were NSD, and the distribution for Stages 2B, 3, and 4 was 25%, 63%, and 9%, respectively. Median (95% CI) time to developing a clinically meaningful outcome was 8.3 (6.2, 10.1), 5.9 (4.1, 6.0), and 2.4 (1.0, 4.0) years for baseline stage 2B, 3, and 4, respectively. We propose pilot biologic and clinical anchors for NSD-ISS. Our results highlight the baseline heterogeneity of individuals currently defined as early PD. Baseline stage predicts time to progression to clinically meaningful milestones. Further research on validation of the anchors in longitudinal cohorts is necessary.

神经元 α-突触核蛋白病 （NSD） 生物学定义和综合分期系统 （NSD-ISS） 提供了一个研究框架，用于识别路易体病理学个体，并根据潜在生物学和日益严重的功能障碍程度对其进行分期。利用来自 PPMI 、 PASADENA 和 SPARK 研究的数据，我们为整个疾病连续体的 NSD-ISS 开发并应用了生物学和临床数据知情定义。根据基线时的生物学、临床和功能锚点定义和分期登记为帕金森病、前驱或健康对照的个体。在这三项研究中，1741 名参与者有 SAA 数据，其中 1030 名 （59%） 是 S+ 与 NSD 一致的。在散发性 PD 中，683/736 （93%） 为 NSD，2B 期、 3 期和 4 期的分布分别为 25% 、 63% 和 9%。基线 2B 期、 3 期和 4 期出现临床有意义结局的中位 （95% CI） 时间分别为 8.3 （6.2， 10.1） 、 5.9 （4.1， 6.0） 和 2.4 （1.0， 4.0） 年。我们提出了 NSD-ISS 的试点生物学和临床锚点。我们的结果突出了目前定义为早期 PD 的个体的基线异质性。基线分期预测进展到具有临床意义的里程碑的时间。有必要进一步研究纵向队列中锚的验证。