遗传背景揭示嗅觉丧失作为帕金森病中通过左旋多巴暴露轨迹预测运动障碍风险的标志物
Genetic context unmasks olfactory loss as a marker for dyskinesia risk via levodopa exposure trajectories in Parkinson's disease.
文献信息
| PMID | 42727510 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Zhiying Zhang |
| 作者单位 | Department of Neurology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. |
| 期刊 | Parkinsonism & related disorders |
| SCI 分区 | Q1 |
| IF | 4.4 |
| 研究类型 | 临床研究 · 临床 |
| 所属专科 | 耳科 |
中文摘要
背景： 嗅觉障碍在帕金森病（PD）中很常见，但其对左旋多巴诱导的运动障碍（LID）的预后价值仍不确定。我们研究了遗传背景是否改变嗅觉-LID关联，以及左旋多巴暴露如何影响这种关系。
方法： 我们分析了来自1254名早期PD参与者的纵向PPMI数据（921例散发性；333例遗传携带者，包括GBA、LRRK2和其他变异）。使用宾夕法尼亚大学嗅觉识别测试将基线嗅觉分类为嗅觉正常、嗅觉减退或嗅觉丧失。结局是从运动症状发作到首次LID的时间。Cox模型测试了嗅觉与遗传学的交互作用，并依次调整平均、单点和时变左旋多巴等效日剂量（LEDD），同时调整发病年龄、性别、基线MDS-UPDRS第三部分和Hoehn和Yahr分期。
结果： 在整个队列中，嗅觉类别与LID无关（P = 0.607）。在遗传性PD中，嗅觉减退（HR 1.88，95% CI 1.16-3.06；P = 0.011）和嗅觉丧失（HR 2.19，95% CI 1.32-3.64；P = 0.003）与更高的LID风险相关，而在散发性PD中未观察到显著关联（P ≥ 0.099）。在未调整LEDD时，遗传与嗅觉的交互作用显著（嗅觉减退：HR 2.71，P = 0.002；嗅觉丧失：HR 2.61，P = 0.004）。在考虑LEDD随时间的变化后，这些交互作用减弱但仍约为两倍（嗅觉减退：HR 2.00，P = 0.049；嗅觉丧失：HR 2.04，P = 0.054）。时变LEDD与LID强烈相关。
结论： 嗅觉障碍主要与遗传性PD中的LID相关，并且在考虑纵向左旋多巴暴露后这种模式仍然存在。这些发现支持嗅觉在PD中具有情境依赖而非普遍的预后作用。
英文摘要
BACKGROUND: Olfactory impairment is common in Parkinson's disease (PD), but its prognostic value for levodopa-induced dyskinesia (LID) remains uncertain. We examined whether genetic background modifies the olfaction-LID association and how levodopa exposure influences this relationship.
METHODS: We analyzed longitudinal PPMI data from 1254 participants with early PD (921 sporadic; 333 genetic carriers, including GBA, LRRK2, and other variants). Baseline olfaction was classified as normosmia, hyposmia, or anosmia using the University of Pennsylvania Smell Identification Test. The outcome was time from motor symptom onset to first LID. Cox models tested olfaction-by-genetics interactions with sequential adjustment for average, point, and time-varying levodopa equivalent daily dose (LEDD), adjusting for age at onset, sex, baseline MDS-UPDRS Part III, and Hoehn and Yahr stage.
RESULTS: Olfactory category was not associated with LID across the whole cohort (P = 0.607). In genetic PD, hyposmia (HR 1.88, 95% CI 1.16-3.06; P = 0.011) and anosmia (HR 2.19, 95% CI 1.32-3.64; P = 0.003) were associated with higher LID hazard, whereas no significant associations were observed in sporadic PD (P ≥ 0.099). Genetic-by-olfaction interactions were significant without LEDD adjustment (hyposmia: HR 2.71, P = 0.002; anosmia: HR 2.61, P = 0.004). After accounting for changes in LEDD over time, these interactions were attenuated but remained approximately two-fold (hyposmia: HR 2.00, P = 0.049; anosmia: HR 2.04, P = 0.054). Time-varying LEDD was strongly associated with LID.
CONCLUSIONS: Olfactory impairment was associated with LID primarily in genetic PD, and this pattern persisted after accounting for longitudinal levodopa exposure. These findings support a context-dependent rather than universal prognostic role of olfaction in PD.