Locus coeruleus network architecture of Alzheimer's disease vulnerability

摘要：蓝斑（LC）被认为是最早积累的区域之一 过度磷酸化的tau蛋白第一个预缠结沉积发生在年轻的成年人，到40岁，LC是 几乎所有的尸检病例都受到了影响这些tau蛋白聚集发生在最早的皮质参与之前， 50岁左右的内嗅皮层，从那里发展到边缘系统和其他皮层区域。的事实 这种高度可预测的病理进展的解剖模式发生在沿着连接的区域， 表明LC-大脑连接是导致最早的脆弱性的机制之一， 阿尔茨海默病（AD）中tau的积累和传播。立法会广泛预测， 使隔离区域之间的通信的整合和协调的皮层。然而，在这方面， 尽管tau在每个40岁以上的人的LC中无处不在，但并不是每个人都会去 因此，为了确保预防试验在这些早期阶段更有效， 这对于区分处于AD风险中的个体与面对病理学保持弹性的个体至关重要。到 为了克服这一障碍，我们需要识别与AD相关的LC大规模网络架构模式 漏洞与赋予AD恢复能力的漏洞。这将有助于更深入地了解网络 与健康或病理性衰老相关的变化，改善早期检测，并有助于识别 有风险的人纳入预防试验。本提案的总体目标是， 通过识别特定的LC网络模式，了解LC特定脆弱性的生物背景 与赋予弹性的那些相比，有助于对AD的脆弱性，并绘制相关的遗传性状。我们 假设LC整合大脑网络的能力的选择性退化与AD相关， 病理学将揭示脆弱和有弹性的LC皮层网络结构布局，这将是 分别与AD相关的认知下降或弹性相关。为了实现这一目标，我们将在多个... 模式LC tau-脆弱集群，通过利用独特的大型7 T fMRI成人寿命脑干队列， 新的血浆AD-生物标志物数据。从LC集群中出现的网络结构将在 这个7 T fMRI数据集和两个大规模的NIA资助的，丰富的多模态纵向数据集，哈佛 大脑老化研究和ADNI。我们将研究以下目标：1）识别解剖脆弱性， tau蛋白沿着LC喙尾轴的分布及其与年龄、性别和载脂蛋白E的关系; 病理学对LC-皮质网络架构的模式，并识别风险与弹性模式; 3） 表征与风险和弹性LC相关的tau扩散谱的遗传脑转录组， 皮质网络模式拟议的研究是创新的，可以导致重大突破， 通过将检测转移到更早的时间点并提供新的招募策略或目标， 在疾病的早期阶段，当脑损伤尚未不可逆转时，使用治疗方法。

ABSTRACT: The locus coeruleus (LC) is considered to be one of the earliest regions accumulating hyperphosphorylated tau. The first pretangle deposits occur in young adulthood, and by age 40 the LC is affected in nearly every case at autopsy. These tau aggregates occur before the earliest cortical involvement in the entorhinal cortex around age 50, from where they progress to limbic and other cortical regions. The fact that this highly predictable anatomic pattern of pathology progression occurs along regions that are connected suggests that LC-brain connectivity is one of the mechanisms contributing to the earliest vulnerability of accumulation and propagation of tau in Alzheimer's disease (AD). The LC has widespread projections to the cortex enabling the integration and coordination of communication between segregated regions. However, even though, tau is omnipresent in the LC of every person above age 40, not everyone will head down to an irreversible AD path. Thus, to ensure that prevention trials are more effective in these early stages, it will be critical to distinguish individuals at risk of AD versus those who remain resilient in the face of pathology. To overcome this barrier, we need to discern LC large-scale network architectural patterns associated with AD vulnerability versus those conferring resiliency to AD. This will provide a deeper understanding of network changes related to healthy or pathological aging, improve early detection and contribute to identifying individuals at-risk for inclusion in prevention trials. The overall goal of this proposal is to characterize and understand the biological background of LC's specific vulnerability by identifying specific LC- network patterns contributing to vulnerability to AD versus those that confer resiliency, and map associated genetic traits. We hypothesize that associating the selective degradation of the LC's capacity to integrate brain networks with AD pathology will uncover vulnerable and resilient LC-cortical network architectural layouts, which will be associated with AD-related cognitive decline or resiliency, respectively. To achieve this, we will generate multi- modal LC tau-vulnerable clusters by utilizing a unique large 7T fMRI adult lifespan brainstem cohort with novel plasma AD-biomarker data. The architecture of networks emerging from LC clusters will be examined in this 7T fMRI dataset and in two large-scale NIA-funded, rich multi-modal longitudinal datasets, the Harvard Aging Brain Study and ADNI. We will examine the following aims: 1) To identify the anatomic vulnerability to tau along the rostro-caudal axis of the LC and its association with age, sex and APOE; 2) To relate AD pathology to patterns of LC-cortical network architecture, and identify at-risk versus resilient patterns; 3) To characterize the genetic brain transcriptome of tau spreading profiles associated with at-risk and resilient LC- cortical network patterns. The proposed research is innovative and can result in a significant breakthrough for the field by shifting detection to earlier time points and providing new enrollment strategies or targets for therapeutic approaches administered earlier in the disease trajectory, when brain damage is not yet irreversible.