Locus coeruleus network architecture of Alzheimer's disease vulnerability

阿尔茨海默病脆弱性的蓝斑网络架构

• 批准号: 10662875
• 负责人: Heidi Irma Jacobs
• 金额: $ 62.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662875
• 关键词: Address; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Anatomy; Atlases; Attention; Autopsy; Biological; Biological Markers; Brain; Brain Injuries; Brain Stem; Brain region; Cells; Cognition; Cognitive; Communication; Data; Data Set; Dedications; Deposition; Detection; Disease; Disease Marker; Disease Progression; Dorsal; Early Diagnosis; Early treatment; Electronic Medical Records and Genomics Network; Electrophysiology (science); Enrollment; Female; Frequencies; Functional Magnetic Resonance Imaging; Funding; Gene Expression; Genetic; Goals; Head; Human; Impaired cognition; Individual; Learning; Life; Longevity; Magnetic Resonance Imaging; Maintenance; Maps; Measures; Medial; Memory; Methods; Mission; Neural Pathways; Neurofibrillary Tangles; Neurons; Pathology; Pathway interactions; Patients; Pattern; Performance; Persons; Plasma; Positron-Emission Tomography; Predisposition; Prevention trial; Primary Prevention; Public Health; Reporting; Research; Rest; Risk; Role; Site; Structure; Temporal Lobe; Time; United States National Institutes of Health; Work; aging brain; apolipoprotein E-4; autosomal dominant Alzheimer' s disease; cognitive performance; cohort; entorhinal cortex; healthy aging; hyperphosphorylated tau; improved; in vivo; innovation; insight; locus ceruleus structure; longitudinal dataset; mild cognitive impairment; multimodality; multisensory; network architecture; novel; pathological aging; pre-clinical; prodromal Alzheimer' s disease; resilience; segregation; sex; targeted treatment; tau Proteins; tau aggregation; tau-1; trait; transcriptome; ultra high resolution; young adult

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.

摘要：蓝斑被认为是最早蓄积的区域之一。 过度磷酸化的tau。第一次椒盐沉积出现在年轻的成年人，到40岁时LC是 在尸检中几乎每一个病例都会受到影响。这些tau聚集体发生在最早的皮质参与之前 大约50岁左右的内嗅皮层，从那里向边缘和其他皮质区域发展。事实是 这种高度可预测的病理进展的解剖模式发生在连接的区域 提示LC-脑连接是导致早期易损性的机制之一。 Tau在阿尔茨海默病(AD)中的积聚和繁殖。立法会有广泛的预测， 允许整合和协调隔离区域之间的通信的皮质。然而， 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 不可逆AD路径。因此，为了确保预防试验在这些早期阶段更有效，将 关键是要区分阿尔茨海默病的风险个体和那些面对病理仍有韧性的人。至 克服这一障碍，我们需要了解与AD相关的LC大规模网络体系结构模式 脆弱性与那些赋予AD复原力的人。这将加深对网络的理解 与健康或病理性衰老相关的变化，改善早期发现并有助于识别 包括在预防试验中的高危个人。这项提案的总体目标是将 通过识别特定的LC网络模式了解LC特定脆弱性的生物学背景 导致阿尔茨海默病易感性的基因与那些赋予复原力并定位相关遗传特征的基因相比。我们 假设LC整合大脑网络的能力选择性下降与AD有关 病理学将揭示易受攻击且具有弹性的LC皮质网络架构布局，它将 分别与阿尔茨海默病相关的认知衰退或复原力有关。为了实现这一目标，我们将产生多个 通过利用独特的大型7T fMRI成人寿命脑干队列建立LC tau易受攻击簇模型 新的血浆AD生物标志物数据。我们将在中研究LC群集中出现的网络体系结构 这个7T功能磁共振数据集和两个由NIA资助的大型、丰富的多模式纵向数据集，哈佛大学 脑老化研究和ADNI。我们将检查以下目标：1)确定存在的解剖漏洞 Lc吻尾轴tau及其与年龄、性别和载脂蛋白E的关系；2)与AD的关系 对LC-皮质网络结构的模式进行病理学分析，并确定风险模式与恢复性模式；3) 描述与高危和恢复性LC相关的tau传播特征的遗传脑转录组 大脑皮层网络模式。这项拟议的研究具有创新性，可以在以下方面取得重大突破 通过将检测转移到更早的时间点并为以下项目提供新的注册战略或目标 当脑损伤还不是不可逆转的时候，在疾病发展轨迹的早期给予治疗方法。