Indices of Motor Synergies as Early Biomarkers of Parkinson's Disease

摘要 帕金森病（PD）是一种常见的神经系统疾病，由多巴胺的进行性丢失引起， 在黑质产生神经元治疗PD的主要问题之一是缺乏早期治疗。 生物标志物将为治疗的实际决策提供关键信息， 针对个别患者的预防计划。我们的主要目标是证明电机的稳定性指标 行动（协同作用指数）可以而且应该作为基于理论的、定量的和客观的行动来使用 PD的生物标志物。我们最近的研究使用不受控流形（UCM）假设的框架， 量化协同作用的研究表明，PD患者表现出协同作用受损（ 行动准备工作中调整协同作用的能力受损（预期 协同效应调整，ASA）。在少数PD I期（Hoehn-Yahr）患者中，协同作用和 在涉及身体部位的行动中发现了ASA，但没有疾病的临床体征。这些结果 这表明，研究协同作用可能会产生客观的生物标志物，能够检测和量化 运动功能受损的PD，可能是敏感的前运动症状阶段的疾病。我们 我计划通过研究一组I期药物初治患者来收集试验数据以支持这一假设 （Hoehn-Yahr）的PD。测试药物初治患者将允许消除PD的影响， 长期暴露于药物对无症状四肢的影响。我们还计划确定 多巴胺替代疗法对这些指标的影响。我们的主要具体假设是：（1）药物- 初治PD I期患者将显示协同指数降低和ASA缩短、延迟， 在有症状和无症状的手/臂中与健康对照相比;和（2）这些 指数将对多巴胺替代药物敏感。两个具体目标将检验主要假设。 目的1：证明和量化有症状和无症状患者协同控制的变化 新诊断、药物初治HY I期PD患者的四肢。我们将量化多指指数 合力稳定合力多关节合力稳定双手轨迹 四肢我们预计，与对照组相比，两侧的协同作用指数将类似地降低。 我们还预测PD患者ASA延迟和减少。目标2：证明和量化有效性 多巴胺替代疗法在改善PD患者协同控制中的作用。研究描述如下： Aim-1将在服用卡比多巴/左旋多巴25/100常规后一小时重复，这是治疗的金标准。 多巴胺能替代我们计划显示药物对协同指数的积极影响， 如果成功，这些结果将有助于我们优化长期前瞻性研究的设计， 通过前瞻性随访，检验多指和多关节协同作用改变的预后价值。 一个大型的早期PD患者群体，探讨协同指数如何预测 出现临床症状，例如在受影响较小的身体一侧出现症状， 姿势不稳步态僵硬 任务 我们认为上肢协同作用受损 反映了协同控制机制的普遍中断，这后来导致了 其他身体部位，包括参与姿势和运动任务的部位。

ABSTRACT Parkinson's disease (PD) is a common neurological disorder caused by progressive loss of dopamine- producing neurons in the substantia nigra. One of the main problems in treating PD is the lack of early biomarkers that would provide crucial information for making practical decisions on treatment and prevention plans for individual patients. Our main goal is to demonstrate that indices of stability of motor actions (indices of synergies) can and should be used as theory-based, quantitative, and objective biomarkers of PD. Our recent studies using the framework of the uncontrolled manifold (UCM) hypothesis to quantify synergies have shown that PD patients demonstrate impaired synergies (low stability of action) and impaired ability to adjust synergies in preparation to action (delayed and reduced anticipatory synergy adjustments, ASAs). In a few patients at stage-I (Hoehn-Yahr) of PD, changes in synergies and ASAs were seen during actions involving body parts without clinical signs of the disease. These results suggest that studying synergies may yields objective biomarkers that are able to detect and quantify impaired motor function in PD and may be sensitive to pre-motor-symptom stages of the disease. We plan to collect pilot data to support this hypothesis by studying a group of drug-naïve patients at stage-I (Hoehn-Yahr) of PD. Testing drug-naïve patients will allow disambiguating effects of PD from possible effects of long-term exposure to drugs on the non-symptomatic extremities. We also plan to determine the effects of dopamine replacement therapy on these indices. Our main specific hypotheses are: (1) Drug- naïve patients with PD stage-I will show reduced synergy indices and shorter, delayed ASAs as compared to healthy controls in both symptomatic and non-symptomatic hands/arms; and (2) These indices will be sensitive to dopamine-replacement drugs. Two specific aims will test the main hypotheses. Aim 1: To demonstrate and quantify changes in synergic control in symptomatic and asymptomatic extremities of newly diagnosed, drug-naïve HY stage-I PD patients. We will quantify indices of multi-finger synergies stabilizing total force and multi-joint synergies stabilizing hand trajectory in both upper extremities. We expect the synergy indices to be reduced similarly on both sides compared to controls. We also predict delayed and reduced ASAs in PD. Aim 2: To demonstrate and quantify the effectiveness of dopamine-replacement therapy in improving synergic control in PD patients. Studies described under Aim-1 will be repeated one hour after taking carbidopa/levodopa 25/100 regular, gold standard for dopaminergic replacement. We plan to show positive effects of the drug on the synergy indices across If successful, these results will help us to optimize design of a longer prospective study that would test the prognostic value of changed multi-finger and multi-joint synergies by following prospectively a large group of early-stage PD patients over several years to explore how synergy indices predict the occurrence of clinical symptoms such as emergence of symptoms on the less-affected body side, postural instability, and freezing of gait. tasks. We view the impaired synergies in the upper extremities as early reflections of a general disruption of the mechanisms of synergic control, which later leads to effects in other body parts including those involved in postural and locomotion tasks.