Enhancing Cognitive Resilience In Parkinson's Disease: Role Of Antiaging Protein Klotho

项目总结 这是一份申请以患者为导向的研究事业发展奖(K23)的申请书。 Nijee Luthra是一位专门研究运动障碍的神经学家。帕金森氏症患者的数量 疾病(PD)预计将增长到大流行的比例，与PD相关的认知恶化将 在这个人口的大多数人中占了上风。为此提出的综合职业发展和研究计划 K23奖的动机是越来越多的人意识到迫切需要确定目标路径 帕金森病患者的认知功能障碍。运动具有很强的抗衰老作用，并能影响帕金森病患者的认知结果 但其潜在机制仍不清楚。识别对运动做出反应的生物标记物，以及它们如何 结合认知和潜在的疾病病理可能阐明对抗的关键机制 认知能力下降。这项提议的重点是长寿激素klotho，作为一种生物标志物，可能会调节 运动带来的益处并有助于认知韧性。Klotho已被证明可以增强认知能力， 衰老和神经退行性变小鼠模型的突触可塑性和脑体积。卢特拉博士和她 研究小组最近还表明，klotho与PD患者更好的认知功能有关。而克洛索 水平随着年龄的增长而降低，在帕金森病患者中，体育锻炼显著增加了健康成年人的klotho水平。 运动是否会增加帕金森病患者的klotho，并防止认知能力下降，目前尚不清楚。为此， 这项研究计划的目的是：1)了解它与认知的积极联系，现在调查是否 Klotho修改PD病理的潜在标记物，以及2)同时，设计一项先导性研究以确定 帕金森氏症患者运动后klotho增加，并与认知能力的改善有关。回答 这些问题将突出klotho作为运动相关生物标记物和新途径的潜力。 目标是认知功能障碍。 研究计划的补充是临床设计和实施的教学和实践培训。 多模式生物标志物和认知的试验、先进的生物统计学方法以及分析和解释 评估。为了实现本次研究和培训的目标，应聘者组织了一次指导 在临床试验和运动干预方面拥有数十年经验的团队，以及在生物标志物方面的专业知识 以及帕金森病患者的认知功能障碍。完成这项研究计划和培训目标将使 成为一名专注于研究的独立临床调查员以促进其职业生涯的候选人 策略，如运动和多个相关的生物标记物，调节帕金森病患者的认知弹性。

PROJECT SUMMARY This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) by Dr. Nijee Luthra, a neurologist specializing in movement disorders. As the number of people with Parkinson’s disease (PD) is expected to grow to pandemic proportions, cognitive deterioration associated with PD will prevail in a majority of this population. The integrated career development and research plan proposed for this K23 award is motivated by an increasing awareness of the urgent need to identify pathways that target cognitive impairment in PD. Exercise has potent anti-aging effects and can influence cognitive outcomes in PD but its underlying mechanisms remain unclear. Identifying biomarkers that respond to exercise, and how they associate with cognition and underlying disease pathology may elucidate key mechanisms for countering cognitive decline. This proposal focuses on longevity hormone klotho as a biomarker that may mediate exercise-induced benefits and contribute to cognitive resilience. Klotho has been shown to enhance cognition, synaptic plasticity, and brain volumes in mouse models of aging and neurodegeneration. Dr. Luthra and her team have also recently shown that klotho associates with better cognitive function in PD patients. While klotho levels decrease with aging and in PD, physical exercise robustly increases klotho levels in healthy adults. Whether exercise increases klotho in PD and protects against cognitive decline is not yet known. To this end, the aims of this research proposal are: 1) knowing its positive link with cognition, to now investigate whether klotho modifies underlying markers of PD pathology, and 2) in parallel, design a pilot study to determine if klotho increases in response to exercise in PD and correlates with improved cognitive abilities. Answers to these questions would highlight the potential of klotho as an exercise-related biomarker and as a new pathway for targeting cognitive dysfunction. The research plan is complemented by didactic and practical training in design and conduct of clinical trials, advanced biostatistical methods, and analysis and interpretation of multimodal biomarkers and cognitive assessments. To accomplish the goals of this research and training, the candidate has assembled a mentoring team with decades of experience in clinical trials and exercise interventions, along with expertise in biomarkers and cognitive impairment in PD. Completion of this research plan and training objectives will allow the candidate to advance her career in becoming an independent clinical investigator focused on investigating strategies such as exercise and multiple related biomarkers that mediate cognitive resilience in PD.