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

• 批准号: 10319913
• 负责人: James Morley
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319913
• 关键词: Accelerometer; 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; Clinical; Clinical Management; Clinical Trials; Cognitive; Corpus striatum structure; Data; Deterioration; Development; Diagnosis; Disease; Disease Progression; Dopamine; Dopamine Receptor; Dropout; Early Diagnosis; Early Intervention; Economic Burden; Enrollment; Exercise; Exercise Therapy; Exhibits; Future; Gait; Gender; Health Benefit; Home; Image; Impairment; Incidence; Individual; Infrastructure; Intervention; Intervention Trial; Left; Link; Measures; Medicine; Mental Depression; Modeling; Modification; Monitor; Mood Disorders; Morbidity - disease rate; Motor; Movement; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Natural History; Neurodegenerative Disorders; Neuronal Plasticity; Olfactory dysfunction; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Population; Post-Traumatic Stress Disorders; Randomized; Randomized Clinical Trials; Recovery; Rehabilitation therapy; Reporting; Research; Risk; Role; Sample Size; Sampling; Serum; Serum Markers; Signal Transduction; Sleep Disorders; Smell Perception; Strenuous Exercise; Stress Tests; Substantia nigra structure; Symptoms; Testing; Time; Toxic effect; Uric Acid; VO2max; Veterans; Walking; Withdrawal; associated symptom; base; cardiovascular fitness; cohort; cost; disease diagnosis; disorder risk; dopamine transporter; dopaminergic neuron; epidemiology study; exercise intervention; expectation; fitness test; follow-up; high risk; improved; middle age; motor disorder; motor function improvement; motor symptom; neuron loss; non-motor symptom; off-label use; persistent symptom; pre-clinical; prevent; programs; prospective; public health relevance; putamen; rate of change; screening; symptom treatment; symptomatic improvement

 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.

 产品说明： 帕金森病（PD）是一种无法治愈的神经退行性疾病，影响约100万美国成年人和约80，000名退伍军人。PD在其长期病程中由于运动和非运动症状导致显著的发病率，仅在美国每年的经济负担就达140亿美元。与PD中多巴胺能神经元损失相关的运动症状可以用多巴胺替代药物暂时改善，但是缺乏和迫切需要延迟或预防神经元损失的疾病修饰疗法。运动作为一种改善疾病的疗法是有希望的，因为它保护PD动物模型中的多巴胺能神经元，并且与PD患者的神经可塑性指标相关。不幸的是，黑质中超过一半的多巴胺能神经元在运动症状发生之前就已经丢失，这使得很难及早识别患者，从而从潜在的疾病改善中获益。 治疗早期“前驱”PD可以使用非运动特征来识别，包括嗅觉功能障碍和其他生物标志物，如多巴胺转运蛋白（DaT）脑成像异常，这些异常在运动症状出现前数年就很明显。然而，如果不首先确定高风险个体进行筛查，这些策略在人群水平上实施将是困难和昂贵的。通常处方的多巴胺阻断抗精神病药物会导致使人衰弱的PD样运动功能障碍，这是很难治疗的，在一些患者中，这一发现可能作为一种“压力测试”，用于在多巴胺能网络正常出现之前很久就发现症状。在药物诱导的帕金森综合征患者中识别前驱PD为早期干预提供了一个独特且未探索的机会。在拟议的研究中，我们将采用分层筛选策略，在药物诱导的帕金森病患者中进行廉价和非侵入性的嗅觉测试，然后在嗅觉障碍患者中进行DaT成像，以确定一组假定为前驱PD的患者。然后将假定前驱期PD的受试者随机分配至家庭运动干预（通过远程活动监测器确认每周有氧步行{5}次）或不进行干预。在这个队列中，我们将评估：1）使用标准临床测量方法，运动对药物诱导的帕金森综合征运动功能的短期症状影响（统一帕金森病评定量表）和定量步态评估; 2）通过比较定量DaT成像的变化率，在52周运动后潜在的疾病改善效果;和3）使用一组涉及运动和/或PD风险的血清生物标志物（包括脑源性神经营养因子、尿酸和载脂蛋白A1），运动诱导的变化的机制和生化相关性。将使用独立样本t检验和调整年龄和性别的线性混合效应模型评估组间变化率的差异。我们的初步数据表明，在药物诱导的帕金森综合征中，嗅觉障碍和异常DaT成像之间存在很强的相关性。基于允许20%脱落的把握度计算，我们将使用嗅觉测试筛选约250例药物诱导的帕金森症受试者，预计约88例将出现异常DaT成像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综合征患者前驱PD将使我们能够确定哪些人处于危险之中，描述疾病进展的自然史，并在PD的最早阶段评估适当的管理策略。与未经证实的药物干预相比，运动作为一种公认的疾病改善疗法提供了显着的优势，包括成本，易于获得和缺乏毒性，特别是如果提供足够早，具有有意义的临床影响。