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

摘要 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），但潜在的机制尚不清楚。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 骨骼肌和认知障碍的关系被确定为优先事项。正如最近更新的 欧洲老年人肌肉减少症工作组（EWGSOP）将肌肉减少症定义为衰老- 不良肌肉变化的相关积累，最终导致肌肉衰竭，其最佳特征为 肌肉力量差。与ADRD相关的肌肉减少症和ADRD可能与调节失调有关。 犬尿氨酸在骨骼肌中的代谢。犬尿氨酸是色氨酸代谢物，具有神经毒性或 神经保护作用。活动诱导的骨骼肌收缩可能通过降低ADRD的发生率来保护ADRD。 神经毒性犬尿氨酸在大脑中的积累，其作用受活动诱导的肌肉调节 宫缩 在这项研究中，我建议测量犬尿氨酸代谢物的血浆浓度在社区居住， 老年人，以确定身体活动，骨骼肌强度， 基线和两年后的神经认知结果。我的主要假设是缺乏体力活动 骨骼肌改变和肌肉减少症，其功能特征是肌肉力量差， 通过神经毒性犬尿氨酸的积累而分子化。神经毒性犬尿氨酸的蓄积增加 ADRD风险，这反映在更高浓度的血浆神经丝光（NfL）-ADRD的生物标志物， 神经退化和认知能力下降。如果体力活动、骨骼 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 进一步研究了针对骨骼肌治疗ADRD的疗法。幸运的是，我有 一个独特的机会，通过利用现有的老年人队列来解决这个研究问题， 基线和2年观察性测量基于腕动计的身体活动、身体表现， 以及可用于犬尿氨酸测定的血浆。 该项目的目标与GEMSSTAR的目标密切相关，以支持初级医生-科学家 在老年病学和医学亚专业之间架起桥梁--在这种情况下，神经病学和神经心理学--成为 老龄化研究的未来领导者完成这些目标将支持我的专业发展 目标，概述了在这个GEMSSTAR应用程序，通过发展跨专业的专业知识，在两个 常见的老年综合征：肌肉减少症和ADRD。我会在选拔中培养专业技能 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 网络.这项工作的结果将作为随后的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功能有有益影响。 功能和ADRD生物标志物。总之，该项目和GEMSSTAR的支持将是至关重要的， 促进我作为跨学科领导人在老龄化研究的发展。

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.