Canary in a coal mine: locus coeruleus, norepinephrine signaling and dementia

该提案的长期目标是开发神经退行性疾病风险的功能性测量， 蓝斑（LC）功能。LC是神经化学物质去甲肾上腺素的脑干来源 （NE）。拟议的工作可能会确定潜在的LC或NE相关的目标，以预防神经退行性疾病。 疾病这与国家老龄化研究所的使命--改善老年人的健康--高度相关。 美国人，因为像AD和PD这样的神经退行性疾病是一个非常重要且不断增长的负担， 对老年人和整个医疗保健系统都是如此。该提案的具体目标是建立 任务诱发的瞳孔反应（其是LC神经元活动的已知代理）、神经元活动和任务诱发的瞳孔反应之间的联系 LC中的密度，增加LC中NE信号传导的天然存在的遗传多态性，以及整体 认知功能该建议的具体目标是：1）确定任务的幅度是否- 在听觉注意任务中诱发的瞳孔反应与老年人的认知表现有关 2）确定LC中神经黑色素MRI信号强度的共享和独特贡献， 任务诱发的瞳孔反应的幅度预测整体认知得分，注意力得分， 认知储备; 3）确定任务诱发的瞳孔反应或神经黑色素MRI是否 信号强度在有和没有adra 2b（α2B肾上腺素受体）缺失变体的个体之间存在差异。 为了实现这些目标，我们建议招募，测试和基因型100人年龄在65-85。该人群 将包括大约50个具有adra 2b缺失变体的个体。我们将评估认知功能 使用NIH认知成套测验和认知储备量表，并测量任务的幅度- 在简单的注意力任务中诱发瞳孔反应。最后，个体将被给予神经黑色素 核磁共振扫描。我们假设任务诱发的瞳孔反应的幅度将呈正相关 LC中的神经元密度，以及更大的瞳孔反应和更多的神经黑色素都将与 更好的认知表现和更高的认知储备。此外，我们假设， adra 2b缺失变体将具有更大的瞳孔反应、更多的神经黑色素和更好的认知能力 比那些没有表现。

The long-term goal of this proposal is to develop a functional measure of risk for neurodegenerative disease, based on locus coeruleus (LC) function. The LC is the brainstem source of the neurochemical norepinephrine (NE). The proposed work may identify potential LC- or NE-related targets for prevention of neurodegenerative disease. This is highly relevant to the National Institute on Aging's mission to improve the health of older Americans, since neurodegenerative diseases like AD and PD represent a very significant and growing burden to older individuals and to the healthcare system at large. The particular goal of this proposal is to establish links between task-evoked pupillary responses (which are a known proxy for LC neuronal activity), neuronal density in the LC, naturally-occurring genetic polymorphisms which increase NE signaling in the LC, and global cognitive functioning. The specific aims for this proposal are to: 1) to determine whether the amplitude of task- evoked pupillary responses during an auditory attention task is related to cognitive performance among older adults; 2) determine the shared and unique contributions of neuromelanin MRI signal intensity in the LC and the amplitude of task-evoked pupillary response to predicting global cognition scores, attention scores, and cognitive reserve; and 3) to determine whether either task-evoked pupillary responses or neuromelanin MRI signal intensity differ between individuals with and without a deletion variant of adra2b, the α2B adrenoceptor. To achieve these aims, we propose to recruit, test and genotype 100 individuals aged 65-85. This population will include approximately 50 individuals with the adra2b deletion variant. We will assess cognitive function using the NIH Toolbox Cognitive Battery and the Cognitive Reserve Scale and measure the amplitude of task- evoked pupillary responses during a simple attention task. Finally, individuals will be given a neuromelanin MRI scan. We hypothesize that the amplitude of task-evoked pupillary responses will be positively correlated with neuronal density in the LC, and larger pupillary responses and more neuromelanin will both be linked to better cognitive performance and higher cognitive reserve. Furthermore, we hypothesize that individuals with the adra2b deletion variant will have larger pupillary responses, more neuromelanin and better cognitive performance than those without.