Effect of Exercise on Recovery in Drug-Induced Parkinsonism and Parkinson Disease

 说明： 帕金森氏病(PD)是一种无法治愈的神经退行性疾病，影响着大约100万美国成年人和大约8万退伍军人。帕金森病在其漫长的病程中，由于运动和非运动症状而导致显着的发病率，仅在美国每年就造成140亿美元的经济负担。与帕金森病患者多巴胺能神经元丢失相关的运动症状可能会通过多巴胺替代药物而暂时改善，但延缓或防止神经元丢失的疾病修改疗法是缺乏的，而且迫切需要。运动是一种很有前途的疾病修正疗法，因为它保护帕金森病动物模型中的多巴胺能神经元，并与帕金森病患者的神经可塑性测量有关。不幸的是，黑质中一半以上的多巴胺能神经元在运动症状出现之前就已经丢失，这使得很难及早识别患者，从而从潜在的疾病调整中受益。 治疗。早期的“前驱”帕金森病可以通过包括嗅觉障碍在内的非运动特征和其他生物标记物，如多巴胺转运体(DAT)脑成像异常来识别，这些异常在运动症状出现前几年就很明显了。然而，如果不首先确定高危人群进行筛查，在人口层面上实施这些战略将是困难和昂贵的。通常处方的多巴胺阻断抗精神病药物会导致难以治疗的衰弱的帕金森样运动功能障碍，在一些患者中，这种发现可能是一种“压力测试”，用于检测多巴胺能网络的故障，在症状出现之前很久就暴露出来。在药物诱导的帕金森病患者中发现帕金森病的前驱症状，为早期干预提供了一个独特的和未被探索的机会。在拟议的研究中，我们将采用分级筛查策略，对药物诱导的帕金森症患者进行廉价和非侵入性的嗅觉测试，然后对嗅觉障碍患者进行DAT成像，以确定一组假定为前驱PD的患者。然后，假定为帕金森病前驱症状的受试者将被随机分为基于家庭的运动干预(远程活动监测器确认的每周有氧步行{5}次)或不干预。在这个队列中，我们将评估：1)使用标准临床指标(统一帕金森病评定量表)和8周干预后的定量步态评估，运动对药物诱导的帕金森症患者运动功能的短期症状影响；2)通过比较定量数据成像的变化率，评估52周运动后潜在的疾病改善效果；以及3)使用一组与运动和/或PD风险有关的血清生物标记物，包括脑源性神经营养因子、尿酸和载脂蛋白A1，评估运动诱导的变化的机制和生化相关性。组间变化率的差异将使用独立样本t检验和根据年龄和性别调整的线性混合效应模型进行评估。我们的初步数据显示，在药物诱导的帕金森病中，嗅觉障碍和异常的dat成像之间存在很强的相关性。基于允许20%辍学的功率计算，我们将使用嗅觉测试对大约250名药物诱导的帕金森综合征患者进行筛查，预计大约有88名患者的DAT成像异常，并同意参与干预试验。抗精神病药物被广泛用于越来越多的批准适应症和标签外用途，包括双相情感障碍、抑郁症和创伤后应激障碍。研究药物诱导的帕金森病患者的前驱帕金森病将使我们能够识别哪些人处于危险之中，表征进展的自然历史，并在帕金森病的早期阶段评估适当的治疗策略。与未经证实的药物干预相比，运动作为一种可能的疾病修正疗法具有显著的优势，包括成本、易用性和无毒性，特别是如果及早提供并产生有意义的临床影响的话。

 DESCRIPTION: Parkinson's disease (PD) is an incurable neurodegenerative disorder affecting approximately 1 million US adults and about 80,000 Veterans. PD causes significant morbidity due to motor and non-motor symptoms across its prolonged course with an annual economic burden of $14 billion in the US alone. Motor symptoms associated with loss of dopaminergic neurons in PD may be temporarily improved with dopamine replacing medicines, but disease-modifying therapies that delay or prevent neuronal loss are lacking and sorely needed. Exercise is promising as a disease-modifying therapy because it protects dopaminergic neurons in animal models of PD and has been associated with measures of neuroplasticity in PD patients. Unfortunately, more than half of dopaminergic neurons in the substantia nigra are lost before motor symptoms occur making it difficult to identify patients early enough to benefit from potentially disease-modifying therapies. Early "prodromal" PD can be identified using non-motor features including olfactory dysfunction and other biomarkers such as dopamine transporter (DaT) brain imaging abnormalities that are apparent years before motor symptoms. However, these strategies would be difficult and costly to implement on a population level without first identifying high-risk individuals for screening. Commonly prescribed dopamine blocking antipsychotic drugs cause debilitating PD-like motor dysfunction that is difficult to treat, and in some patients this findin may serve as a "stress test" for failing dopaminergic networks unmasking symptoms long before they would normally appear. Identifying prodromal PD among drug-induced parkinsonism patients offers a unique and unexplored opportunity for early intervention. In the proposed studies, we will employ a tiered screening strategy with inexpensive and non-invasive olfactory testing in drug-induced parkinsonism patients followed by DaT imaging in individuals with olfactory impairment to identify a cohort of patients with presumed prodromal PD. Subjects with presumed prodromal PD will then be randomized to a home-based exercise intervention ({5} times weekly aerobic walking confirmed by remote activity monitors) or no intervention. In this cohort, we will assess: 1) Short-term symptomatic effects of exercise on motor function in drug-induced parkinsonism using standard clinical measures (Unified Parkinson's Disease Rating Scale) and quantitative gait assessments after 8 weeks of intervention; 2) a potential disease-modifying effect after 52 weeks of exercise by comparing the rate of change in quantitative DaT imaging; and 3) the mechanisms and biochemical correlates of exercise-induced changes using a panel of serum biomarkers implicated in exercise and/or PD risk including brain-derived neurotrophic factor, uric acid, and apolipoproteinA1. Differences in the rate of change between groups will be assessed using independent samples t-tests and linear mixed-effects models adjusting for age and gender. Our preliminary data demonstrates a strong association between olfactory impairment and abnormal DaT imaging in drug- induced parkinsonism. Based on power calculations allowing for 20% dropout, we will screen approximately 250 drug-induced parkinsonism subjects using olfactory testing, with the expectation that approximately 88 will have abnormal DaT imaging and agree to participate in the intervention trial. Antipsychotic drugs are widely prescribed for a growing list of approved indications and off-label uses including bipolar disorder, depression and post-traumatic stress disorder. Studying drug-induced parkinsonism patients with prodromal PD will allow us to identify which individuals are at risk, characterize the natural history of progression and evaluate appropriate management strategies at the earliest stages of PD. Exercise as a putative disease-modifying therapy offers significant advantages including cost, ease of access and lack of toxicity compared with unproven pharmacologic interventions especially if offered early enough to have meaningful clinical impact.