Long Term Aerobic Exercise to Slow Progression in Parkinson's Disease

长期有氧运动可减缓帕金森病的进展

• 批准号: 10663892
• 负责人: ERGUN Y UC
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10663892
• 关键词: Acetylcholinesterase Inhibitors; Activities of Daily Living; Adverse event; Aerobic; Aerobic Exercise; Aging; American; Animals; Antidepressive Agents; Automobile Driving; Autonomic nervous system disorders; Biological; Biological Markers; Blood Vessels; Brain; Cardiac; Cessation of life; Clinical; Clinical Trials; Cognition; Cognitive; Complex; Corpus striatum structure; Data; Dementia; Disease; Disease Progression; Fatigue; Health; Human; Immobilization; Impaired cognition; Impairment; Individual; Individual Differences; Infrastructure; Knowledge; Long-Term Effects; Measures; Mediating; Medical; Metabolic; Monitor; Mood Disorders; Motor; Movement; Nerve Degeneration; Operative Surgical Procedures; Outcome; Outcome Measure; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physical therapy; Physiological Processes; Quality of life; Randomized, Controlled Trials; Research; Research Design; Risk; Sample Size; Sleep Disorders; Structure; Symptoms; System; Testing; Time; Tissues; Training; Translations; VO2max; Veterans; Work; brain health; brain tissue; cardiorespiratory fitness; cognitive function; cost; disability; exercise regimen; functional outcomes; improved; improved outcome; indexing; instrumental activity of daily living; mental function; mild cognitive impairment; motor disorder; motor function improvement; motor impairment; motor symptom; neural; non-motor symptom; side effect; societal costs; treatment as usual; trial comparing; white matter

Parkinson's disease (PD) culminates in dementia, immobility, and death at a huge societal cost. Even early in the course, motor and cognitive dysfunction impairs instrumental activities of daily living (IADL). Non-motor symptoms due to fatigue, mood, sleep, and autonomic disorders further reduce quality of life (QoL). DTI shows progressive decline in brain tissue integrity. Usual care of PD centers on medical and surgical treatments relieve motor symptoms, but these cause side effects and lose efficacy over time. Usual treatment for non- motor manifestations with pharmaceuticals (e.g., antidepressants) is symptomatic and not specific for PD. Acetylcholine esterase inhibitors exert modest symptomatic benefits on dementia, but there is no approved treatment for mild cognitive impairment. Physical Therapy is usually prescribed in later stages when mobility impairment ensues. There is no approved standard exercise regimen for PD. There is no cure or disease modifying treatment. Thus, there is a critical need for treatments that provide broad spectrum of benefits and slow PD. Preliminary research suggests that aerobic exercise has potential to meet this need. However, aerobic exercise is demanding and carries some risks. It is unknown if aerobic exercise is more beneficial than usual care in PD in long term due to gaps in our knowledge about the effects of cardiorespiratory fitness (CRF) on brain tissue integrity, motor function, cognition, IADL, QoL, and disease progression. Limitations of current studies include short duration, small sample size, lack or inadequacy of controls, lack of outcome measures for cognition and IADL, and lack of biological markers to measure progression. Our objective in this application is to fill the translational gap by determining the biological, clinical, and functional effects of long term aerobic exercise (LTAE) in PD. Our overall hypothesis is that LTAE improves brain tissue integrity and slows down PD. Our FIRST AIM is to determine the effects of LTAE on clinical features and functional abilities in PD. Our prior 6-month, uncontrolled trial showed preliminary evidence that aerobic exercise improves aspects of motor function, cognition, and QoL in PD, but long term outcomes and implication for functional abilities are unknown. We hypothesize that LTAE will provide sustained improvement in motor function, cognition, and non- motor symptoms with translation of benefits to QoL and IADL. We will test this with a one-year randomized controlled trial (RCT) that compares the effects of moderate aerobic exercise vs usual care. We will use driving as the outcome for IADL. Driving represents an important symbol for independence, and depends on integrity of cognitive and motor systems. Our SECOND AIM is to determine the mechanism of LTAE effects in PD. CRF reflects complex improvements in vascular, cardiac, and metabolic health from aerobic exercise. There is preliminary evidence that higher CRF is associated with better brain health and motor/cognitive function, and that aerobic exercise improves these outcomes. For example, our preliminary study showed improvement of microtissue integrity in the striatum and white matter on DTI, but it is unclear how these changes counteract PD progression over long term. Our hypotheses are: 1) LTAE will improve brain tissue integrity as indexed by DTI, 2) LTAE effects on motor and cognitive function are mediated by changes in brain tissue integrity on DTI, and 3) physiological processes leading to improved CRF from AE are critical to the benefits on the brain tissue integrity and motor/cognitive function. We will test these hypotheses determining the effects of LTAE on CRF and DTI, and the association between individual differences in training-related changes in motor and cognitive function, DTI, and CRF. In summary, our proposal leverages our diverse interdisciplinary team, strong preliminary data and past work, and unique infrastructure to determine if LTAE slows down neurodegeneration and clinical disability in PD.

帕金森病 (PD) 最终导致痴呆、行动不便和死亡，造成巨大的社会成本。甚至早在 运动和认知功能障碍会损害日常生活的工具性活动（IADL）。非电机 疲劳、情绪、睡眠和自主神经紊乱引起的症状进一步降低了生活质量 (QoL)。工贸部显示 脑组织完整性进行性下降。 PD 的常规护理以药物和手术治疗为主 缓解运动症状，但这些会引起副作用并随着时间的推移而失效。非常规治疗 药物（例如抗抑郁药）引起的运动表现是有症状的，并不是帕金森病特有的。 乙酰胆碱酯酶抑制剂对痴呆症有一定的症状缓解作用，但尚未获得批准 治疗轻度认知障碍。物理治疗通常在活动后期进行 随之而来的损害。目前尚无批准的帕金森病标准运动方案。没有治愈方法或疾病 修改治疗。因此，迫切需要能够提供广泛益处和 慢速PD。初步研究表明，有氧运动有潜力满足这一需求。然而， 有氧运动要求很高，并且存在一定的风险。有氧运动是否比有氧运动更有益尚不清楚 由于我们对心肺健康 (CRF) 影响的了解存在差距，需要对帕金森病进行长期常规护理 脑组织完整性、运动功能、认知、IADL、生活质量和疾病进展。当前的限制 研究时间短、样本量小、对照缺乏或不充分、缺乏结果测量 认知和 IADL，并且缺乏衡量进展的生物标记。我们在此应用程序中的目标是 通过确定长期有氧运动的生物学、临床和功能效应来填补转化空白 PD 中的运动（LTAE）。我们的总体假设是 LTAE 可以改善脑组织完整性并减缓 下PD。我们的首要目标是确定 LTAE 对 PD 临床特征和功能能力的影响。 我们之前为期 6 个月的非对照试验显示了初步证据，表明有氧运动可以改善 PD 的运动功能、认知和生活质量，但长期结果和对功能能力的影响是 未知。我们假设 LTAE 将持续改善运动功能、认知和非 运动症状以及对 QoL 和 IADL 的益处。我们将用一年的随机试验来测试这一点 对照试验 (RCT)，比较适度有氧运动与常规护理的效果。我们将使用驾驶 作为 IADL 的结果。驾驶是独立的重要标志，依赖诚信 认知和运动系统。我们的第二个目标是确定 LTAE 对 PD 的影响机制。病例报告表 反映了有氧运动对血管、心脏和代谢健康的复杂改善。有 初步证据表明较高的 CRF 与更好的大脑健康和运动/认知功能相关，并且 有氧运动可以改善这些结果。例如，我们的初步研究表明， DTI 上纹状体和白质的微组织完整性，但尚不清楚这些变化如何抵消 PD 长期进展。我们的假设是：1) LTAE 将改善脑组织完整性，如下所示： DTI，2) LTAE 对运动和认知功能的影响是通过 DTI 上脑组织完整性的变化介导的， 3) AE 导致 CRF 改善的生理过程对于脑组织的益处至关重要 完整性和运动/认知功能。我们将测试这些假设，以确定 LTAE 对 CRF 的影响 和 DTI，以及与训练相关的运动和认知变化的个体差异之间的关联 功能、DTI 和 CRF。总之，我们的提案利用了我们多元化的跨学科团队、强大的 初步数据和过去的工作，以及确定 LTAE 是否减缓神经退行性疾病的独特基础设施 和 PD 的临床残疾。