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

摘要 帕金森氏病(PD)是一种常见的神经系统疾病，由多巴胺进行性丧失引起。 在黑质产生神经元。治疗帕金森病的主要问题之一是缺乏早期的 生物标志物，将提供关键信息，以作出实际的治疗和决策 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(协同效应指数)可以而且应该作为基于理论的、定量的和客观的 帕金森病的生物标志物。我们最近的研究使用了无控制流形(UCM)假说的框架 量化协同效应表明，帕金森病患者表现出协同作用受损(低稳定性 行动)和在准备行动中调整协同作用的能力受损(预期延迟和减少 协同效应调整(Asas)。在少数PD I期(Hoehn-Yahr)患者中，协同作用和 在没有疾病临床症状的情况下，在涉及身体部位的动作中可以看到这种情况.这些结果 提示研究协同效应可能会产生能够检测和量化的客观生物标记物 帕金森病患者运动功能受损，可能对疾病的运动症状前期敏感。我们 计划通过研究一组处于I期的未服用药物的患者来收集支持这一假设的先导数据 (Hoehn-Yahr)。测试药物幼稚的患者将消除帕金森病的影响 长期接触药物对无症状肢体的影响。我们还计划确定 多巴胺替代治疗对上述指标的影响。我们的主要具体假设是：(1)药物- PD-I期的幼稚患者将表现出协同指数降低和更短、延迟的ASA 与有症状和无症状的手/臂的健康对照组进行比较；以及(2) 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：验证和量化有症状和无症状患者协同控制的变化 新诊断的药物天真的HY期帕金森病患者的肢体。我们将对多指指数进行量化 协同稳定总力和多关节协同稳定上半部手部轨迹 四肢。我们预计，与控制措施相比，双方的协同效应指数将出现类似的下降。 我们还预测帕金森病患者的ASA延迟和减少。目标2：论证和量化有效性 多巴胺替代疗法在改善帕金森病患者协同控制中的作用。下描述的研究 AIM-1将在服用卡比多巴/左旋多巴25/100常规后一小时重复，黄金标准为 多巴胺能替代疗法。我们计划展示该药物对以下各项协同指数的积极影响 如果成功，这些结果将帮助我们优化设计一项更长的前瞻性研究，这将 通过前瞻性地跟踪观察改变的多指和多关节协同作用来检验其预后价值 多年来对一大群早期PD患者进行研究，以探索协同指数如何预测 出现临床症状，如症状出现在受影响较小的身体一侧， 姿势不稳，步态僵硬。 任务。 我们认为上肢的协同作用受损早在 反映了协同控制机制的普遍破坏，这后来导致了 身体的其他部分，包括那些涉及姿势和运动任务的部分。

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.