Healthy Skeletal Muscle, Healthy Brain: Are Kynurenine Metabolites the Link?

健康的骨骼肌，健康的大脑：犬尿氨酸代谢物是其中的联系吗？

基本信息

批准号：
10027781
负责人：
Daniel C Parker
金额：
$ 16.1万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10027781
关键词：
Address Adult Affect Age-associated memory impairment Aging Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk American Amino Acids Biological Assay Biological Markers Brain Cognition Communities Data Dementia Development Disease Drug Targeting Elderly European FDA approved Failure Future Geriatrics Goals Health Impaired cognition Intervention Junior Physician K-Series Research Career Programs Knowledge Kynurenine Lead Light Link Lower Extremity Measures Mediating Medical Memory Mentors Metabolism Mind Molecular Muscle Muscle Contraction Nerve Degeneration Neurocognitive Neurology Neuropsychology Neurosciences Osteoporosis Outcome Physical Function Physical Performance Physical activity Plasma Population Prevalence Preventive therapy Preventive treatment Public Health Research Scientist Skeletal Muscle Soft Tissue Disorder Syndrome Tryptophan Update Work actigraphy age related aged base brain health cognitive function cognitive performance cohort dementia risk executive function improved medical specialties muscle strength neurofilament neurotoxic physical inactivity preservation prevent protective effect reduced muscle strength sarcopenia symposium therapeutic target working group

项目摘要

ABSTRACT There is increasing evidence that sarcopenia is a risk factor for Alzheimer’s disease and related dementias (ADRD), but the potential mechanisms are unknown. The significance of this gap was highlighted at the 2019 NIA-sponsored U13 Osteoporosis & Soft Tissue Disorders Conference where improved understanding of the relationship of skeletal muscle and cognitive impairment was identified as a priority. As recently updated by the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia is defined as the aging- related accumulation of adverse muscle changes that culminates in muscle failure and is best characterized by poor muscle strength. Age-related sarcopenia and ADRD may be mechanistically linked by dysregulated kynurenine metabolism in skeletal muscle. Kynurenines are tryptophan metabolites with neurotoxic or neuroprotective effects. Activity-induced skeletal muscle contraction may protect against ADRD by decreasing accumulation of neurotoxic kynurenines in the brain, with effects regulated by activity-induced muscle contractions. In this study, I propose to measure plasma concentrations of kynurenine metabolites in a community-dwelling older adults to determine the relationship between physical activity, skeletal muscle strength, and neurocognitive outcomes at baseline and after two years. My central hypothesis is that physical inactivity leads to skeletal muscle alterations and sarcopenia, characterized functionally by poor muscle strength and molecularly by accumulation of neurotoxic kynurenines. Accumulation of neurotoxic kynurenines increases ADRD risk, which is reflected by greater concentrations of plasma neurofilament light (NfL) – a biomarker of neurodegeneration – and poorer cognitive performance. If the relationship between physical activity, skeletal muscle strength, and cognitive performance is mediated by neurotoxic kynurenine metabolites, that will support further studies investigating therapies directed to skeletal muscle to treat ADRD. Fortunately, I have the unique opportunity to address this research question by leveraging an existing cohort of older adults with baseline and two-year observational measures of actigraphy-based physical activity, physical performance, and cognition as well as plasma available for kynurenine determination. The goal of this project is closely aligned with the GEMSSTAR objective to support junior physician-scientists bridging geriatrics and medical subspecialties – in this case, neurology and neuropsychology – to become future leaders in aging research. Completion of these aims will support my professional development objectives, outlined within this GEMSSTAR application, by developing cross-specialty expertise in two common, co-occurring geriatric syndromes: sarcopenia and ADRD. I will develop expertise in the selection, use, and analysis of neuropsychological assessments and refine my neuroscience mentoring and collaborative networks. Results of this work will serve as preliminary data for a subsequent career development award to evaluate whether interventions that promote neuroprotective metabolites have beneficial effects on cognitive function and ADRD biomarkers. Taken together, this project and GEMSSTAR support will be critical in furthering my development at as transdisciplinary leader in aging-research.

抽象的越来越多的证据表明肌肉减少症是阿尔茨海默病和相关痴呆症的危险因素（ADRD），但潜在机制尚不清楚，这一差距的重要性在 2019 年得到了强调。 NIA 赞助的 U13 骨质疏松症和软组织疾病会议提高了对骨质疏松症和软组织疾病的了解正如最近更新的那样，骨骼肌和认知障碍的关系被确定为优先事项。欧洲老年人肌肉减少症工作组 (EWGSOP)，肌肉减少症被定义为衰老- 不良肌肉变化的相关积累最终导致肌肉衰竭，其最佳特征是年龄相关的肌肉减少症和 ADRD 可能与失调有机械联系。犬尿氨酸在骨骼肌中的代谢是具有神经毒性或毒性的色氨酸代谢物。活动引起的骨骼肌收缩可以通过减少ADRD来预防ADRD。神经毒性犬尿氨酸在大脑中积聚，其影响受活动诱导的肌肉调节宫缩。在这项研究中，我建议测量社区居住的犬尿氨酸代谢物的血浆浓度老年人以确定体力活动、骨骼肌力量和我的中心假设是身体不活动会导致基线和两年后的神经认知结果。骨骼肌改变和肌肉减少症，其功能特征是肌肉力量差和分子上通过神经毒性犬尿氨酸的积累增加神经毒性犬尿氨酸的积累。 ADRD 风险，通过较高浓度的血浆神经丝光 (NfL) 来反映，这是一种生物标志物神经退行性变——与身体活动、骨骼之间的认知能力较差有关。肌肉力量和认知能力是由神经毒性犬尿氨酸代谢物介导的，这将支持进一步研究针对骨骼肌治疗 ADRD 的疗法幸运的是，我有。通过利用现有的老年人群体来解决这一研究问题的独特机会基于体动记录的身体活动、身体表现的基线和两年观察测量，认知以及血浆可用于犬尿氨酸测定。该项目的目标与 GEMSSTAR 支持初级医师科学家的目标密切相关连接老年病学和医学亚专业（在本例中为神经病学和神经心理学），成为老龄化研究的未来领导者的完成这些目标将支持我的专业发展。通过开发两个领域的跨专业知识，实现本 GEMSSTAR 应用程序中概述的目标常见的、同时发生的老年综合症：肌肉减少症和 ADRD 我将在选择方面发展专业知识，使用和分析神经心理学评估并完善我的神经科学指导和协作这项工作的结果将作为后续职业发展奖的初步数据。评估促进神经保护代谢物的干预措施是否对认知产生有益影响总的来说，该项目和 GEMSSTAR 的支持对于实现这一目标至关重要。促进我作为衰老研究跨学科领导者的发展。