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

运动协同指数作为帕金森病的早期生物标志物

• 批准号: 9213760
• 负责人: XUEMEI HUANG
• 金额: $ 22.69万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213760
• 关键词: Affect; American; Biological Markers; Body part; Carbidopa; Clinical; Clinical Research; Cohort Studies; Data; Development; Devices; Disease; Dopamine; Drug Exposure; Effectiveness; Ensure; Environment; Exposure to; Fingers; Foundations; Freezing; Future; Gait; Goals; Gold; Hand; Hour; Intervention; Joints; Levodopa; Limb structure; Locomotion; Long-Term Effects; Measurement; Methods; Motor; Movement; Muscle; Neurons; Newly Diagnosed; Parkinson Disease; Patients; Performance; Pharmaceutical Preparations; Physicians; Population; Posture; Preparation; Prevention; Prevention strategy; Prospective Studies; Replacement Therapy; Research Personnel; Side; Staging; Substantia nigra structure; Symptoms; Testing; Upper Extremity; Work; arm; base; design; drug testing; falls; improved; indexing; individual patient; motor impairment; motor symptom; nervous system disorder; novel; prognostic value; prospective; relating to nervous system; research clinical testing; theories; user-friendly

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.

抽象的 帕金森氏病（PD）是由多巴胺逐渐丧失引起的一种常见神经系统疾病 在黑质中产生神经元。治疗PD的主要问题之一是缺乏早期 生物标志物将提供至关重要的信息，以做出治疗和 针对个别患者的预防计划。我们的主要目标是证明电动机稳定性指标 行动（协同索引）可以并且应该用作基于理论的，定量和客观的 PD的生物标志物。我们最近使用不受控制的歧管（UCM）假设的框架的研究 为了量化协同作用，已经表明PD患者表现出协同作用受损（低稳定性 动作）和调整协同作用以准备行动的能力受损（延迟和减少了预期 协同调整，ASA）。在PD的I期（Hoehn-Yahr）的一些患者中，协同作用的变化和 在涉及身体部位的行动中看到ASA，没有疾病的临床迹象。这些结果 建议研究协同作用可能会产生能够检测和量化的客观生物标志物 PD的运动功能受损，可能对疾病的运动前症状敏感。我们 计划通过研究一组未接受药物的患者，以收集试点数据来支持这一假设。 Pd的（Hoehn-Yahr）。对药物的测试患者将允许歧义PD的歧义作用 长期接触药物对非症状肢体的影响。我们还计划确定 多巴胺替代疗法对这些指数的影响。我们的主要特定假设是：（1）药物 - 幼稚的PD患者I阶段I将显示出降低的协同指数，并且较短，延迟ASAS 与有症状和无症状的手/手臂中的健康对照相比； （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。 目标1：证明和量化有症状和无症状的协同控制变化 新诊断的，未经药物的hy阶段PD患者的四肢。我们将量化多指的索引 协同稳定总力和多接头协同稳定手部轨迹 四肢。我们预计，与对照组相比，双方的协同指数将类似地降低。 我们还预测了PD中的延迟和减少ASA。目标2：证明和量化有效性 多巴胺替代疗法在改善PD患者的协同控制方面。所描述的研究 AIM-1将在服用Carbidopa/Levodopa 25/100常规，金标准后重复一小时 多巴胺能替代。我们计划展示该药物对跨越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一项更长的前瞻性研究的设计 通过前瞻性地测试多手指和多接头协同作用的预后价值 大量的早期PD患者多年来探讨协同指数如何预测 出现临床症状，例如症状紧急症状在受影响较小的身体方面， 姿势不稳定和步态冻结。 任务。 我们在上肢时认为上肢的协同作用受损 对协同控制机制的一般破坏的反射，后来导致影响 其他身体部位，包括涉及姿势和运动任务的部位。