Neural and Energetic Drivers of Performance and Perceived Fatigability in Older Adults

摘要 较高的易疲劳性，即某人由于疲劳而在身体或精神上受到限制的程度，是常见的， 社区居住的老年人的残疾。虽然与疾病相关的疲劳可以通过以下方式改善： 针对潜在的疾病，老年人疲劳的原因和定义还不清楚 治疗方法也不可行。对老年人的研究显示， 功能和心肺功能;健身和力量训练可以改善疲劳，但好处往往是 受限于动力不足、努力减少和运动因素受损（负重疼痛、关节炎）。 可吸收性似乎受到神经能量过程的影响，特别是纹状体多巴胺（DA）信号传导 和脑氧代谢率。新兴的药理学和行为干预促进这些 神经能量过程似乎也降低年轻健康成人的疲劳性。然而，这些发现 不能被翻译到老年人，因为神经能量对疲劳的贡献还没有被研究。 我们建议解决这一知识差距，并检查多系统的贡献（大脑，肌肉， 心肺）到体能疲劳（PPF），定义为在一段时间内的性能下降， 标准化的体力劳动。我们的总体假设是，较高的纹状体DA，相关网络的活动， 大脑能量代谢预测老年人较低的PPF;我们还提出，这些神经标志物，单独 并结合解释PPF超出了肌肉能量和心肺功能的预测。 我们最近优化的神经能量成像方案使用最先进的MRI-PET扫描仪， 同时测量纹状体DA（PET）、非侵入性脑O2代谢率（基于全脑MRI的O2 提取分数、血流量）、纹状体网络的静息状态活动;和任务相关激活（功能性近- 在双重任务期间前额叶皮层的红外光谱）。我们目前正在收集该方案的基线， 150名参与者参加了SOMMA（肌肉，流动性和衰老研究），这是一项为期3年的纵向持续研究。我们提出 将这些神经影像学测量与客观PPF（在快节奏400米步行过程中减慢）相关联， 纵向和纵向，历时3年。我们利用SOMMA已经获得的措施：a） 感知疲劳性（在5分钟跑步机步行结束时的感知劳累性评级;匹兹堡疲劳性量表）; B） 肌肉线粒体功能（活检，P31磁共振波谱）和质量; c）心肺 功能（VO 2峰值，心肺运动试验）; d）运动因素（睡眠，疼痛，关节炎，BMI，合并症）。 这项创新研究具有很高的潜在影响，因为它将量化人体内的能量和代谢过程。 大脑、肌肉和心肺系统，单独和组合，与疲劳性有关。本研究 提供了一个前所未有的机会，以成本效益，纵向，多系统评估的决定因素， 体能疲劳。

ABSTRACT Higher fatigability, the degree to which someone is physically or mentally limited due to fatigue, is common and disabling in community-dwelling older adults. While fatigue associated with a disease can be ameliorated by targeting the underlying condition, the causes and definitions of fatigability in older age are not well understood and treatments are not available. Studies in older adults show associations with lower muscle mitochondrial function and cardiopulmonary fitness; fitness and strength training can improve fatigability, but benefits are often limited by poor motivation, reduced effort, and impaired locomotor factors (weight bearing pain, arthritis). Fatigability appears influenced by neuro-energetic processes, and specifically striatal dopamine (DA) signaling and cerebral metabolic rate of oxygen. Emerging pharmacologic and behavioral interventions promoting these neuro-energetic processes also appear to reduce fatigability in young healthy adults. However, these findings cannot be translated to older adults because the neuro-energetic contributions to fatigability have not been studied. We propose to address this gap in knowledge and examine the multi-systemic contribution (brain, muscle, cardiopulmonary) to physical performance fatigability (PPF), defined as performance decline during a standardized physical task. Our overarching hypothesis is that higher striatal DA, related networks’ activity, and brain energy metabolism predict lower PPF in older adults; we also propose that these neural markers, individually and in combination explain PPF beyond what is predicted by muscle energetic and cardiopulmonary function. Our recently optimized neuro-energetic imaging protocol uses a state-of-the-art MRI-PET scanner to simultaneously measure striatal DA (PET), cerebral metabolic rate of O2 non-invasively (total brain MRI-based O2 extraction fraction, blood flow), resting state activity of striatal networks; and task-related activation (functional near- infrared spectroscopy of prefrontal cortex during dual tasks). We are currently collecting this protocol at baseline in 150 participants of SOMMA (Study of Muscle, Mobility and Aging),a 3 year longitudinal ongoing study. We propose to relate these neuroimaging measures with objective PPF (slowing down during the fast paced 400m walk), cross- sectionally and longitudinally over 3 years. We leverage the measures that SOMMA is already obtaining: a) perceived fatigability (rating of perceived exertion at end of 5-min treadmill walk; Pittsburgh Fatigability Scale); b) muscle mitochondrial function (biopsy, P31magnetic resonance spectroscopy) and mass; c) cardiopulmonary function (VO2 peak, cardio-pulmonary exercise test); d) locomotor factors (sleep, pain, arthritis, BMI, comorbidities). This innovative research has high potential impact, because it will quantify energetic and metabolic processes in brain, muscle, and cardiopulmonary systems, separately and in combination, in relation to fatigability. This study offers an unprecedented opportunity for a cost-effective, longitudinal, multi-system assessment of determinants of physical performance fatigability.