Neurobiological drivers of mobility resilience: the dopaminergic system

摘要 到了老年，走路变得更慢，自动化程度也更低，需要更多的注意力和前额叶资源。 与年龄相关的行走障碍的常见原因是脑部小血管疾病(CSVD)和 外围系统。我们最近发现，大约20%的老年人即使在 存在常见的运动风险因素，因此看起来很有弹性。我们的研究表明黑质纹状体 多巴胺(DA)系统可能是这种弹性的来源之一。我们假设较高的黑质纹状体DA 神经传递通过与感觉运动更高的连接性来驱动对运动危险因素的弹性 因此，减少了前额叶调节的运动控制，恢复了行走的自动控制。 黑质纹状体DA系统的弹性是一个新的和非常有前途的研究领域。与血管不同 损伤和脑结构损伤，DA神经传递是潜在的可修改的，从而提供了新的 减少与年龄相关的行走障碍的方法。虽然对人类的福祉有很大的潜在价值 随着年龄的增长，在同时测量黑质纹状体的情况下，对与年龄相关的流动性的认识存在严重差距 DA系统、cSVD和外周系统损害。我们的目标是： 目标1：从横向和纵向两个方面量化与发展援助相关的对机动性恢复的贡献。 我们假设黑质纹状体DA神经传递预测正常和双侧行走能力 任务调节并减少cSVD和外周系统损害对行走的负面影响 性能。 目的2：评估与DA相关的横断面和纵向行走的自动控制。我们 假设黑质纹状体DA神经传递与感觉运动网络的连通性协同作用 预测步行时较高的步行能力和较低的前额叶激活。 作为测试DA对弹性的影响的第一个翻译步骤，我们建议收集 慢走老年人cSVD和明显与年龄相关的机械性目标投入研究 纹状体DA缺失。探索性目标3：评估L多巴给药1周对连通性的影响 和步态速度作为纹状体DA释放的分子标志物的函数 明显的与年龄相关的纹状体DA丢失。 这项研究的创新之处在于，它超越了对损伤的解释，揭示了弹性因素和 它们的机制是新干预措施的基础。它的影响很大，因为最近的研究结果表明 药物和行为干预可以改善DA信号转导。我们的团队拥有独一无二的专业知识 使用新技术，代表了几十年来在衰老、大脑和机动性研究方面的思想领袖。

ABSTRACT In older age, walking becomes slower and less automated, requiring more attention and prefrontal resources. Common causes of age-related walking impairments are cerebral small vessel disease (cSVD) and changes in peripheral systems. We have recently discovered that ~20% of older adults maintain fast gait speed even in the presence of common locomotor risk factors, thus appearing resilient. Our work suggests that the nigrostriatal dopamine (DA) system may be a source of this resilience. We hypothesize that higher nigrostriatal DA neurotransmission drives resilience to locomotor risk factors via higher connectivity with sensorimotor networks, thus reducing prefrontal-mediated motor control and restoring automated control of walking. Resilience due to the nigrostriatal DA system is a novel and highly promising area of inquiry. Unlike vascular lesions and brain structural impairments, DA neurotransmission is potentially modifiable, thereby offering novel approaches to reduce age-related walking impairments. Although of substantial potential value to wellbeing in aging, there is a critical gap in knowledge of age-related mobility with simultaneous measures of nigrostriatal DA system, cSVD and peripheral system impairments. Our aims are: AIM 1: Quantify the DA-related contribution to mobility resilience, cross-sectionally and longitudinally. We hypothesize that nigrostriatal DA neurotransmission predicts walking performance, during usual and dual task conditions and reduces the negative effects of cSVD and peripheral system impairment on walking performance. AIM 2: Assess DA-related automated control of walking, cross-sectionally and longitudinally. We hypothesize nigrostriatal DA neurotransmission acts synergistically with connectivity of sensorimotor networks to predict higher walking performance and lower prefrontal activation while walking. As a first translational step in testing the effects of DA on resilience, we propose to collect pilot data for a mechanistic target-engagement study in slow-walking older adults with cSVD and pronounced age-associated striatal DA loss. Exploratory AIM 3: To assess the effects of 1 week of L-DOPA administration on connectivity and gait speed as a function of molecular markers of striatal DA release in non-resilient elderly with pronounced age-associated striatal DA losses. This research is innovative in that it goes beyond explaining impairments, to revealing resilience factors and their mechanisms as the basis for novel interventions. It has high impact because recent findings suggest that pharmacological and behavioral interventions can improve DA signaling. Our team has unique expertise in the use of novel technologies and represents decades as thought leaders in the study of aging, brain and mobility.