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

摘要 较高的疲劳性，即一个人由于疲劳而身体或精神受到限制的程度，是很常见的 在社区居住的老年人中残疾。虽然与疾病相关的疲劳可以通过以下方式改善 针对潜在的情况，老年人疲劳性的原因和定义还没有很好地理解 而且目前还没有治疗方法。对老年人的研究表明，肌肉线粒体水平较低 机能和心肺健康；健身和力量训练可以改善疲劳性，但好处通常是 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)。 肥胖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。 以及大脑的氧气代谢率。新兴的药理学和行为干预措施促进了这些 神经能量过程似乎也降低了年轻健康成年人的疲劳性。然而，这些发现 不能翻译到老年人身上，因为神经能量对疲劳性的贡献还没有研究过。 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)到体能疲劳性(PPF)，定义为在 标准化的体力任务。我们的主要假设是纹状体DA较高，相关网络的活动，以及 脑能量代谢预测老年人的PPF较低；我们还提出，这些神经标志物，单独 并结合对PPF的解释，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 同时无创性测量纹状体DA(PET)、脑O2代谢率(基于全脑MRI的O2 提取分数，血流)，纹状体网络的静息状态活动；以及与任务相关的激活(功能近 双重任务期间前额叶皮质的红外光谱)。我们目前正在以基准收集此协议， 150名参与者参加了Somma(肌肉、活动能力和衰老研究)，这是一项为期3年的纵向正在进行的研究。我们建议 为了将这些神经成像测量与客观PPF(在快节奏400米步行中减速)联系起来，交叉- 横向和纵向均超过3年。我们利用Somma已经获得的措施：a) 感知疲劳性(5分钟跑步机步行结束时的感知疲劳度评级；匹兹堡肥胖度量表)；b) 肌肉线粒体功能(活组织检查、P31磁共振波谱)和质量；c)心肺 功能(VO2峰值、心肺运动试验)；d)运动因素(睡眠、疼痛、关节炎、体重指数、合并疾病)。 这项创新研究具有很高的潜在影响，因为它将量化能量和代谢过程 大脑、肌肉和心肺系统，单独和组合，与疲劳性有关。本研究 为经济高效、纵向、多系统评估决定因素提供了前所未有的机会 体能疲劳性。

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.