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

这项提议的长期目标是开发一种神经退行性疾病风险的功能性衡量标准， 基于蓝斑(LC)功能。LC是神经化学物质去甲肾上腺素的脑干来源 (NE)。拟议的工作可能确定潜在的LC或NE相关的靶点，以防止神经退行性变 疾病。这与国家老龄研究所改善老年人健康的使命高度相关 美国人，因为像阿尔茨海默病和帕金森氏症这样的神经退行性疾病是一个非常严重且不断增长的负担 对老年人和整个医疗体系都是如此。这项提案的具体目标是建立 任务诱发的瞳孔反应(这是LC神经元活动的已知指标)、神经元之间的联系 LC中的密度，自然发生的遗传多态增加LC中的NE信号，以及全球 认知功能。这项建议的具体目的是：1)确定任务的幅度是否- 老年人在听觉注意任务中诱发的瞳孔反应与认知表现有关 2)确定神经黑素MRI信号强度在LC和 任务诱发的瞳孔反应的幅度预测全局认知分数、注意力分数和 认知储备；以及3)确定任务诱发的瞳孔反应或神经黑色素MRI α2B受体ADRA2b缺失变异体的个体之间信号强度不同。 为了实现这些目标，我们建议招募100名年龄在65-85岁之间的人进行测试和基因分型。这群人 将包括大约50名具有ADRA2b缺失变体的人。我们将评估认知功能 使用NIH工具箱认知成套测验和认知储备量表，测量任务的幅度- 在一个简单的注意力任务中唤起瞳孔反应。最后，个体将被注射一种神经黑色素 核磁共振扫描。我们假设任务诱发的瞳孔反应的幅度将是正相关的 随着LC内神经元密度的增加，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，我们假设具有 ADRA2b缺失变异体将有更大的瞳孔反应，更多的神经黑色素和更好的认知 比那些没有的人表现得更好。

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.