Predictors of progression to freezing of gait in Parkinson's disease

帕金森病进展为冻结步态的预测因子

• 批准号: 9132362
• 负责人: COLUM D MACKINNON
• 金额: $ 40.4万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132362
• 关键词: Address; Anisotropy; Area; Ballistics; Behavior; Biological Markers; Biomechanics; Brain Stem; Cell Nucleus; Cerebellum; Clinical; Clinical Research; Data; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Early Intervention; Etiology; Fiber; Freezing; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Gait; Gait abnormality; Generations; Goals; Health; Heterogeneity; Image; Impairment; Individual; Levodopa; Link; Magnetic Resonance Imaging; Maps; Measures; Mediating; Morbidity - disease rate; Motor; Motor Cortex; Movement; Muscle; Musculoskeletal Equilibrium; Nerve Degeneration; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Posture; Process; REM Sleep; Resistance; Rest; Risk; Role; Series; Severities; Sleep; Sleep Disorders; Sleep disturbances; Staging; Study Section; Symptoms; Thalamic structure; Upper Extremity; base; cholinergic neuron; cohort; critical period; design; disorder subtype; effective therapy; falls; frontal lobe; insight; locomotor control; mortality; motor symptom; neuroimaging; neurophysiology; prevent; prospective; research study; therapy development

 DESCRIPTION (provided by applicant): Postural instability and gait disturbances, including freezing of gait are common, disabling and poorly understood symptoms that afflict approximately half of all patients with Parkinson's disease. With disease progression these symptoms become resistant to treatment and are major causes of falls, immobility and increased morbidity. Currently there are no effective treatments. Degeneration of the pedunculopontine nucleus, a region in the brainstem that controls locomotor pattern generation and postural tone, has been hypothesized to mediate the pathogenesis of postural instability and gait dysfunction. The pedunculopontine nucleus also plays a role in suppressing muscle activity during rapid eye movement (REM) sleep. Thus, the loss of the pedunculopontine nucleus should manifest as disturbances in both sleep and gait. This project will conduct a series of experiments to establish that neurodegenerative processes that disrupt the control muscle activity during REM sleep are closely linked to the development and progression of treatment-resistant postural instability and gait dysfunction. Quantitative assessments of sleep and motor function (gait, gait initiation, postural stability), in conjunction with magnetic resonance imaging measures of structural (from diffusion- weighted imaging) and functional connectivity (from resting-state functional imaging) of the region of the pedunculopontine nucleus, will be obtained in a cohort of patients with early stage Parkinson's disease. These patients will be followed for three years to map the progression of changes in sleep, motor function and organization of brainstem locomotor pathways. We hypothesize that the loss of suppression of muscle activity during REM sleep will be predictive of the rate of progression of treatment-resistant motor features of disease and changes in structural and functional connectivity of the PPN region. Establishment of a link between REM sleep disorder and the development of treatment-resistant motor features of disease will help to identify individuals at risk of developing these symptoms. Since REM sleep disturbances can often be recognized years or decades before the emergence of parkinsonian motor symptoms, this may provide a critical period for early intervention to slow or prevent disease progression. Overall the study section was very enthusiastic about the focus of this application which addresses an area of high significance, but specific concerns reduced the overall level of enthusiasm.

 描述（由申请人提供）：姿势不稳和步态障碍（包括步态冻结）是常见的、致残的和知之甚少的症状，大约有一半的帕金森病患者患有这些症状。随着疾病进展，这些症状对治疗产生抵抗力，是跌倒、不动和发病率增加的主要原因。目前尚无有效的治疗方法。桥脚核（脑干中控制运动模式生成和姿势张力的区域）的退化被假设介导姿势不稳定和步态功能障碍的发病机制。桥脚核还在快速眼动 (REM) 睡眠期间抑制肌肉活动中发挥作用。因此，桥脚核的丧失应表现为睡眠和步态障碍。该项目将进行一系列实验，以确定在快速眼动睡眠期间破坏控制肌肉活动的神经退行性过程与难治性姿势不稳定和步态功能障碍的发生和进展密切相关。将在一组早期帕金森病患者中获得睡眠和运动功能（步态、步态启动、姿势稳定性）的定量评估，结合桥脚核区域的结构（来自扩散加权成像）和功能连接（来自静息态功能成像）的磁共振成像测量。这些患者将被跟踪三年，以绘制睡眠、运动功能和脑干运动通路组织变化的进展情况。我们假设，快速眼动睡眠期间肌肉活动抑制的丧失将预示着疾病的难治性运动特征的进展速度以及 PPN 区域结构和功能连接的变化。建立快速眼动睡眠障碍与疾病的难治性运动特征之间的联系将有助于识别有出现这些症状风险的个体。由于快速眼动睡眠障碍通常可以在帕金森运动症状出现前数年或数十年被发现，因此这可能为早期干预以减缓或预防疾病进展提供关键时期。总体而言，研究部分对该应用程序的重点非常热衷，该应用程序解决了一个非常重要的领域，但具体的担忧降低了总体热情水平。