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

 描述(申请人提供)：姿势不稳和步态障碍，包括步态冻结，是常见的、致残的和鲜为人知的症状，困扰着大约一半的帕金森氏病患者。随着疾病的发展，这些症状变得对治疗产生抵抗力，并成为跌倒、行动不便和发病率增加的主要原因。目前还没有有效的治疗方法。桥脑脚核是脑干中控制运动模式生成和姿势张力的区域，已被假设参与姿势不稳定和步态功能障碍的发病机制。桥脑脚核在快速眼动(REM)睡眠中也起着抑制肌肉活动的作用。因此，桥脑脚核的丢失应该表现为睡眠和步态的障碍。该项目将进行一系列实验，以确定在REM睡眠期间扰乱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发展密切相关。对睡眠和运动功能(步态、步态启动、姿势稳定性)的定量评估，以及对桥脚核区域结构(通过扩散加权成像)和功能连通性(通过静息状态功能成像)的磁共振成像测量，将在一组早期帕金森病患者中获得。这些患者将被跟踪三年，以绘制睡眠、运动功能和脑干运动路径组织的变化进展图。我们假设，REM睡眠期间肌肉活动抑制的丧失将预测耐药运动疾病的进展速度以及PPN区域结构和功能连接的变化。在快速眼动睡眠障碍和疾病的抗药性运动特征的发展之间建立联系将有助于识别有可能出现这些症状的个人。由于快速眼动睡眠障碍通常可以在帕金森氏症运动症状出现前几年或几十年被发现，这可能为早期干预提供一个关键时期，以减缓或防止疾病进展。总体而言，研究部分对这一应用的重点非常热情，因为它涉及一个具有很高意义的领域，但具体的关切降低了总体热情水平。

 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.