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

项目摘要 这是一个应用程序的指导病人为导向的研究职业发展奖（K23）博士。 Nijee Luthra是一位专门研究运动障碍的神经学家。帕金森症患者的数量 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 在大多数人口中占主导地位。为此提出的综合职业发展和研究计划 K23奖的动机是越来越意识到迫切需要确定针对 认知功能障碍运动具有有效的抗衰老作用，并可影响PD的认知结果 但其潜在机制尚不清楚。识别对运动做出反应的生物标志物，以及它们如何 与认知和潜在疾病病理学相关的疾病可能阐明对抗 认知能力下降这项建议的重点是长寿激素klotho作为一种生物标志物，可能介导 运动诱发的益处，并有助于认知恢复力。Klotho已被证明可以增强认知能力， 突触可塑性，以及衰老和神经退行性小鼠模型的脑体积。卢瑟拉医生和她 研究小组最近还表明，Klotho与PD患者更好认知功能有关。当克洛托 水平随着年龄的增长而下降，在PD中，体育锻炼强烈地增加健康成年人的klotho水平。 运动是否会增加PD中的klotho并防止认知能力下降尚不清楚。为此目的， 本研究建议的目的是：1）了解其与认知的积极联系，现在调查是否 klotho修改了PD病理学的基础标志物，2）同时，设计一项试点研究以确定是否 klotho在PD患者中对运动的反应增加，并与认知能力的改善相关。的答案 这些问题将突出klotho作为运动相关生物标志物和新途径的潜力。 针对认知功能障碍 该研究计划是补充教学和实践培训的设计和进行临床 试验，先进的生物统计方法，以及多模式生物标志物和认知功能的分析和解释。 评估。为了完成这项研究和培训的目标，候选人已经组建了一个指导小组， 团队拥有数十年的临床试验和运动干预经验，沿着生物标志物方面的专业知识 和认知功能障碍完成本研究计划和培训目标将使 候选人推进她的职业生涯，成为一名独立的临床研究者，专注于研究 策略，如运动和多种相关的生物标志物，介导PD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.