疾病进程图进展标志物从孤立性REM睡眠行为障碍转移至非RBD前驱期α-突触核蛋白病：一项纳入1,499名参与者的PPMI研究

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中文摘要

疾病进程图（DCM）通过三个个体化标志物总结每位参与者的轨迹： 参与者在生命早期达到某一疾病阶段的时间（时间偏移，τ）、此后进展的速度（加速，α），以及运动变化是否超前于认知变化（标志物间距，ω）。这些标志物近期被证明可追踪孤立性REM睡眠行为障碍（iRBD）的进展，但它们是否适用于无RBD的前驱期人群尚不清楚。我们研究了来自帕金森病进展标志物倡议（PPMI）的1,499名非RBD前驱期参与者（1,088名嗅觉减退者，411名基因携带者；187名表型转换者），每人均有至少2次纵向MoCA和MDS-UPDRS-III评估。我们在该队列中训练了一个新的DCM，并单独应用了已发表的iRBD模型且未作任何改动。两个模型对参与者的排序几乎相同（Spearman ρ = 0.87-0.97），表明iRBD图谱无需重新校准即可重现。更早的起病（较低的τ）和更快的进展（较高的α）均与较低的基线纹状体多巴胺转运体结合相关（n = 1,426），复制了iRBD的生物学特征，并且α-突触核蛋白种子扩增（SAA）阳性参与者的进展更快（n = 1,375；Benjamini-Hochberg校正后P < 0.001）。转换者的模型估计起病时间早于非转换者，且在删失所有诊断后访视后这一差异仍然存在（校正后P = 0.003），而他们更快的进展则不然（校正后P = 0.08）。运动变化倾向于超前于认知变化，尤其是在基因携带者中，但这是最不稳健的信号，且在限制随访后未能持续存在。DCM进展标志物从iRBD转移至非RBD前驱期α-突触核蛋白病，并保留多巴胺能和分子效度，支持其作为非RBD前驱期表型中连续、个体化终点的应用。

英文摘要

A Disease Course Map (DCM) summarizes each participant's trajectory with three individual markers: how early in life a participant reaches a given disease stage (time-shift, τ), how fast it then progresses (acceleration, α), and whether motor change runs ahead of cognitive change (intermarker spacing, ω). These markers were recently shown to track progression in isolated REM sleep behavior disorder (iRBD), but whether they apply to prodromal populations without RBD is unknown. We studied 1499 non-RBD prodromal participants from the Parkinson's Progression Markers Initiative (1088 hyposmia, 411 genetic carriers; 187 phenoconverters), each with ≥2 longitudinal MoCA and MDS-UPDRS-III assessments. We trained a new DCM in this cohort and separately applied the published iRBD model unchanged. The two models ranked participants almost identically (Spearman ρ = 0.87-0.97), showing the iRBD map is recoverable without recalibration. Earlier onset (lower τ) and faster progression (higher α) were both associated with lower baseline striatal dopamine-transporter binding (n = 1426), replicating the iRBD biology, and progression was faster in α-synuclein seed-amplification (SAA)-positive participants (n = 1375; Benjamini-Hochberg-adjusted P < 0.001). Converters had an earlier model-estimated onset than non-converters, and this difference persisted after censoring all post-diagnosis visits (adjusted P = 0.003), whereas their faster progression did not (adjusted P = 0.08). Motor change tended to run ahead of cognitive change, particularly in genetic carriers, but this was the least robust signal and did not persist when follow-up was restricted. DCM progression markers transfer from iRBD to non-RBD prodromal alpha-synucleinopathy and retain dopaminergic and molecular validity, supporting their use as continuous, individual-level endpoints in non-RBD prodromal phenotypes.