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

运动对药物引起的帕金森病和帕金森病恢复的影响

基本信息

批准号：
9078666
负责人：
James Morley
金额：
--
依托单位：
PHILADELPHIA VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078666
关键词：
Accelerometer Accounting Adult Adverse effects Aerobic Aerobic Exercise Affect Age Animal Model Anterior Anti-Cholinergics Antipsychotic Agents Area Biochemical Biological Markers Bipolar Disorder Blood Tests Brain imaging Brain scan Brain-Derived Neurotrophic Factor Cardiovascular system Clinical Clinical Management Clinical Trials Cognitive Corpus striatum structure Data Deterioration Development Diagnosis Disease Disease Progression Dopamine Dopamine Receptor Dropout Drops Early Diagnosis Early Intervention Economic Burden Enrollment Epidemiologic Studies Exercise Exercise Therapy Exhibits Functional disorder Future Gait Gender Health Benefit Home environment Image Impairment Incidence Individual Intervention Intervention Trial Label Left Link Measures Medicine Mental Depression Modeling Modification Monitor Mood Disorders Morbidity - disease rate Motor Movement Natural History Neurodegenerative Disorders Neuronal Plasticity Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacotherapy Phase Population Post-Traumatic Stress Disorders Randomized Randomized Clinical Trials Recovery Rehabilitation therapy Reporting Research Research Infrastructure Risk Role Sample Size Sampling Serum Serum Markers Signal Transduction Sleep Disorders Smell Perception Staging Strenuous Exercise Stress Tests Substantia nigra structure Symptoms Testing Time Toxic effect Uric Acid VO2max Veterans Walking Withdrawal base cohort cost disease diagnosis disorder risk dopamine transporter dopaminergic neuron exercise intervention expectation fitness fitness test follow-up high risk improved middle age motor disorder motor function improvement motor symptom neuron loss non-motor symptom persistent symptom pre-clinical prevent programs prospective public health relevance putamen rate of change screening symptom treatment symptomatic improvement

Accelerometer Accounting Adult Adverse effects Aerobic Aerobic Exercise Affect Age Animal Model Anterior Anti-Cholinergics Antipsychotic Agents Area Biochemical Biological Markers Bipolar Disorder Blood Tests Brain imaging Brain scan Brain-Derived Neurotrophic Factor Cardiovascular system Clinical Clinical Management Clinical Trials Cognitive Corpus striatum structure Data Deterioration Development Diagnosis Disease Disease Progression Dopamine Dopamine Receptor Dropout Drops Early Diagnosis Early Intervention Economic Burden Enrollment Epidemiologic Studies Exercise Exercise Therapy Exhibits Functional disorder Future Gait Gender Health Benefit Home environment Image Impairment Incidence Individual Intervention Intervention Trial Label Left Link Measures Medicine Mental Depression Modeling Modification Monitor Mood Disorders Morbidity - disease rate Motor Movement Natural History Neurodegenerative Disorders Neuronal Plasticity Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacotherapy Phase Population Post-Traumatic Stress Disorders Randomized Randomized Clinical Trials Recovery Rehabilitation therapy Reporting Research Research Infrastructure Risk Role Sample Size Sampling Serum Serum Markers Signal Transduction Sleep Disorders Smell Perception Staging Strenuous Exercise Stress Tests Substantia nigra structure Symptoms Testing Time Toxic effect Uric Acid VO2max Veterans Walking Withdrawal base cohort cost disease diagnosis disorder risk dopamine transporter dopaminergic neuron exercise intervention expectation fitness fitness test follow-up high risk improved middle age motor disorder motor function improvement motor symptom neuron loss non-motor symptom persistent symptom pre-clinical prevent programs prospective public health relevance putamen rate of change screening symptom treatment symptomatic improvement

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项目摘要

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.

描述：帕金森氏病（PD）是一种无法治愈的神经退行性疾病，影响了约100万美国成年人和约80,000名退伍军人。 PD由于运动和非运动症状在其长时间的路线上引起了明显的发病率，仅在美国，年度经济伯伦（Burnen）的年度经济伯宁（Burnen）就会在美国。与多巴胺替换药物相关的多巴胺能神经元丧失有关的运动症状可能会暂时改善，但缺乏延迟或预防神经元丧失的疾病改良疗法，并且迫切需要。运动是一种改善疾病的疗法，因为它可以保护PD动物模型中的多巴胺能神经元，并且与PD患者的神经可塑性度量有关。不幸的是，在运动症状发生之前，在底底尼格拉中丢失了一半以上的多巴胺能神经元，因此很难尽早识别出患者，从而从潜在的疾病修饰中受益疗法。可以使用非运动功能（包括嗅觉功能障碍）和其他生物标志物（例如多巴胺转运蛋白（DAT）脑成像异常，这显然是在运动症状前几年，可以使用嗅觉功能障碍和其他生物标志物（例如多巴胺转运蛋白（DAT）脑成像异常）来鉴定早期的“前驱” PD。但是，在不先确定高风险个人进行筛查的情况下，在人群水平上实施这些策略将很难且昂贵。通常开处方的多巴胺阻塞抗精神病药会导致令人衰弱的PD样运动功能障碍，难以治疗，在某些患者中，这种发现可能是对多巴胺能网络失败的“压力测试”，因为多巴胺能网络揭露症状很久以前就会正常出现。在药物诱导的帕金森病患者中鉴定前PD PD为早期干预提供了独特而出乎意料的机会。在拟议的研究中，我们将采用一种分层的筛查策略，在药物诱导的帕金森氏症患者中进行廉价和非侵入性嗅觉测试，然后对嗅觉障碍的患者进行DAT成像，以识别出假定前驱PD患者的同类。然后，具有假定前驱PD的受试者将随机分为家庭运动干预措施（{5}乘以每周的有氧运动步行，通过远程活动监视器确认）或不干预。在此队列中，我们将评估：1）使用标准临床措施（统一的帕金森氏病评级量表）和在干预8周后使用标准临床措施（统一的帕金森氏病评级量表）和定量收集评估，运动对药物诱导的帕金森氏症运动功能的短期症状影响； 2）通过比较定量DAT成像的变化率，在运动52周后产生了潜在的疾病调整作用； 3）使用在运动和/或PD风险中实现的血清生物标志物（包括脑衍生的神经营养因子，尿酸和甲状腺酸而候）中实现的血清生物标志物的机制和生化相关性。将使用独立样本t检验评估组之间变化率的差异，并根据年龄和性别调整线性混合效应模型。我们的初步数据表明，药物诱导的帕金森氏症中嗅觉损伤与异常DAT成像之间存在密切的关联。基于允许20％辍学的功率计算，我们将使用嗅觉测试筛选大约250名药物诱导的帕金森氏症受试者，并期望大约88例具有异常DAT成像并同意参加干预试验。抗精神病药被广泛规定，以越来越多的批准的适应症和标签外用途清单，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氏症患者的前代PD患者将使我们能够确定哪些人处于危险之中，在PD的最早阶段表征了进展的自然历史和评估适当的管理策略。与未经证实的药理学干预措施相比，运动作为一种推定的疾病改良疗法，包括成本，易用性和缺乏毒性，尤其是在足够及早提供以具有有意义的临床影响的情况下。