Neurobiological drivers of mobility resilience: the dopaminergic system

摘要 在老年人中，步行变得更慢，自动化程度更低，需要更多的注意力和前额资源。 与年龄相关的行走障碍的常见原因是脑小血管病（cSVD）和脑血管病变。 外围系统我们最近发现，约20%的老年人保持快速的步态速度，即使在 常见的运动风险因素的存在，从而出现弹性。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。我们假设黑质纹状体DA含量较高 神经传递通过与感觉运动的更高连接性驱动对运动风险因素的恢复力 网络，从而减少前额介导的运动控制和恢复步行的自动控制。 由于黑质纹状体DA系统的弹性是一个新的和非常有前途的调查领域。不像血管 损伤和脑结构损伤，DA神经传递是潜在可修改的，从而提供新的 减少与年龄有关的步行障碍的方法。虽然对人类的福祉具有巨大的潜在价值， 随着年龄的增长，与年龄相关的流动性知识与黑质纹状体的同时测量存在着严重的差距。 DA系统、cSVD和外围系统损伤。我们的目标是： 目标1：量化DA相关的贡献，流动性弹性，横截面和纵向。 我们假设，黑质纹状体DA神经传递预测步行性能，在平时和双 任务条件，并减少cSVD和外周系统损伤对行走的负面影响 性能 目的2：评估DA相关的自动控制行走，横截面和纵向。我们 假设黑质纹状体DA神经传递与感觉运动网络连接协同作用 来预测更高的行走性能和行走时更低的前额叶激活。 作为测试DA对弹性影响的第一步，我们建议收集试点数据， 对患有cSVD且明显与年龄相关的慢走老年人进行的机械目标参与研究 纹状体DA丢失探索性目的3：评估1周左旋多巴给药对连接性的影响 和步态速度作为纹状体DA释放的分子标志物的函数， 与年龄相关的纹状体DA损失 这项研究是创新的，因为它超越了解释损伤，揭示弹性因素， 他们的机制作为新的干预措施的基础。它具有很高的影响力，因为最近的研究结果表明， 药理学和行为干预可以改善DA信号传导。我们的团队在以下方面拥有独特的专业知识： 使用新技术，并代表几十年来在老龄化，大脑和流动性研究的思想领袖。

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.