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：坐基因座（LC）被认为是累积的最早区域之一 高磷酸化的tau。第一个piftangle沉积物出现在成年年轻，到40岁时，LC为 在尸检几乎所有情况下都受到影响。这些tau骨料发生在最早的皮质参与之前 50岁左右的内嗅皮层，从那里发展到边缘和其他皮质区域。事实 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 表明LC-脑连通性是导致最早脆弱性的机制之一 tau在阿尔茨海默氏病（AD）中的积累和传播。 LC对 皮层可以使隔离区域之间的通信集成和协调。然而， 即使Tau在40岁以上的每个人的LC中无所不在，并不是每个人都会前往 不可逆的广告路径。因此，为确保预防试验在这些早期阶段更有效，将是 面对病理学的人与那些保持韧性的人与那些保持韧性的人至关重要。到 克服这一障碍，我们需要辨别与广告相关的大规模网络架构模式 脆弱性与赋予AD弹性的脆弱性。这将为网络提供更深入的了解 与健康或病理衰老有关的变化，改善早期检测并有助于识别 个人处于危险中，以纳入预防试验。该提议的总体目标是表征和 通过识别特定的LC-网络模式来了解LC特定漏洞的生物学背景 有助于脆弱性与赋予弹性的广告以及绘制相关的遗传特征的脆弱性。我们 假设将LC与AD集成大脑网络的能力相关联 病理学将发现脆弱且有弹性的LC-Cortical网络架构布局，这将是 分别与与广告相关的认知下降或弹性有关。为了实现这一目标，我们将产生多 通过利用独特的7T fMRI成人寿命脑干队列的模态LC Tau可掩盖簇 新型血浆AD-BIOMARKER数据。从LC簇出现的网络架构将在 这个7T fMRI数据集以及两个大规模的NIA资助，丰富的多模式纵向数据集，哈佛大学 衰老的大脑研究和ADNI。我们将研究以下目的：1）确定解剖脆弱性 沿LC的Rostro-caudal轴及其与年龄，性别和Apoe的关联； 2）关联广告 LC-Cortical网络体系结构模式的病理学，并确定高危与弹性模式； 3）到 表征与处于危险和弹性LC-相关的TAU扩散谱的遗传脑转录组 皮质网络模式。拟议的研究具有创新性，可以为 通过将检测转移到较早的时间点并提供新的入学策略或目标来实现该领域 当脑损伤尚不可逆时，疾病轨迹早些时候采用的治疗方法。