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（LC）被认为是最早积累的区域之一。 过度磷酸化的 tau 蛋白。第一次预缠结沉积发生在青年时期，到 40 岁时，LC 就出现了。 尸检时几乎所有病例都受到影响。这些 tau 蛋白聚集发生在最早的皮质参与之前 50岁左右，内嗅皮层开始发育，从那里发展到边缘和其他皮质区域。事实 这种高度可预测的病理进展解剖模式发生在相连的区域 表明 LC 脑连接是导致早期脆弱性的机制之一 阿尔茨海默病 (AD) 中 tau 蛋白的积累和传播。 LC 广泛预测 皮层能够整合和协调隔离区域之间的沟通。然而， 尽管 tau 蛋白在每个 40 岁以上的人的 LC 中无处不在，但并不是每个人都会选择 不可逆的 AD 路径。因此，为了确保预防试验在早期阶段更加有效，将 对于区分有 AD 风险的个体和面对病理情况仍能保持弹性的个体至关重要。到 为了克服这个障碍，我们需要辨别与 AD 相关的 LC 大规模网络架构模式 脆弱性与赋予AD弹性的那些。这将使您对网络有更深入的了解 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 有风险参加预防试验的个人。该提案的总体目标是描述和描述 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 与那些赋予AD弹性和映射相关遗传特征的因素相比，有助于AD的脆弱性。我们 假设 LC 整合大脑网络能力的选择性退化与 AD 相关 病理学将揭示脆弱且有弹性的 LC 皮质网络架构布局，这将是 分别与 AD 相关的认知能力下降或弹性相关。为了实现这一目标，我们将生成多个 通过利用独特的大型 7T fMRI 成人寿命脑干队列，模态 LC tau 易受影响簇 新的血浆 AD 生物标志物数据。 LC 集群中出现的网络架构将在 这个 7T fMRI 数据集和两个由 NIA 资助的大型、丰富的多模态纵向数据集，哈佛大学 大脑老化研究和 ADNI。我们将研究以下目标：1）确定解剖学上的脆弱性 沿着 LC 头尾轴的 tau 蛋白及其与年龄、性别和 APOE 的关系； 2）关联AD LC 皮质网络架构模式的病理学，并识别风险模式与弹性模式； 3) 至 表征与有风险和有弹性的 LC 相关的 tau 传播谱的遗传脑转录组 皮质网络模式。拟议的研究具有创新性，可以为以下领域带来重大突破： 通过将检测转移到更早的时间点并提供新的注册策略或目标 在疾病轨迹的早期，即脑损伤尚未不可逆转时，采取治疗方法。