Elevated locus coeruleus metabolism as mechanism driving Alzheimer's disease pathology

摘要：阿尔茨海默病(AD)的神经病理特征是β-淀粉样蛋白的堆积 (aβ)和tau蛋白，每种蛋白在疾病进展过程中都有自己的典型地形。事实是， 这种病理进展的解剖模式发生在解剖上相连的区域，这表明 这种病理通过互联互通传播。最近针对A-β的治疗结果令人失望 AD的前驱阶段表明了早期干预的重要性，并预示着一个令人兴奋的机会： 通过专注于与病理最初传播相关的机制，疾病的进展可能会在 最早的阶段，在不可逆转的损伤之前已经影响了大脑。尸检数据显示， 蓝斑(LC)是tau最早影响的区域之一：到40岁时，LC中可以检测到tau聚集。 80%的个体，在新皮质Aβ或tau之前。在50岁时，几乎50%的人患有牛磺酸 TEC的病理改变，提示tau已经从LC进展到TEC。这个 支持当前研究的科学前提来自动物和我们的脑脊液(CSF)工作， 证明LC代谢的升高可能驱动tau的过度磷酸化和增殖 到遥远的、相互连接的地区，并引发认知能力下降。这项提案的总体目标是审查 LC代谢及其与tau在AD连续体所有阶段的进展的关系，以及与模型 连接性与tau的进展和认知功能下降有关。为了实现这一目标，我们将决心 到目前为止阻碍人类活体评估这些关系的两个方法学障碍：1) 在考虑18F-氟脱氧葡萄糖PET和2)分辨率的同时测量LC代谢 在许多交叉的脑干纤维中识别连接LC和TEC的纤维束。结合这些状态- 在两个NIA资助的RICH中使用Aβ、tau(正电子发射计算机断层扫描和脑脊液)和认知的纵向数据的新方法 多模式纵向数据集、哈佛老龄化脑研究和阿尔茨海默病神经成像 这一举措将使我们能够检查以下目标：目标1)检查LC新陈代谢的演变 抗体/tau分期或诊断组的功能及其与tau随时间累积的关系；目标A)至 在两个队列中以一致的方式识别和验证连接LC和TEC的区域；并检查 跨AD连续体的LC-TEC束完整性；以及目标2B)模拟较低LC-TEC- TEC连接性和tau在LC代谢和认知衰退之间的关系上的增加。一起， 这些目的提高了我们对初始tau繁殖的机制基础的理解，以及 它与认知的关联性。拟议的研究是创新的，可以对我们的 对阿尔茨海默病的病理生理学的理解，也可以通过以下方式为该领域带来重大突破 将检测转移到更早的时间点，并为治疗方法提供新的目标或策略 在疾病发展轨迹的早期，当大脑损伤还不是很严重的时候。

ABSTRACT: The neuropathologic hallmarks of Alzheimer's disease (AD) are accumulations of beta-amyloid (Aβ) and tau proteins, that each have their own typical topography during disease progression. The fact that this anatomic pattern of pathology progression occurs along regions that are anatomically connected, suggests that pathology spreads via connectivity. Disappointing results from recent therapeutic efforts targeting Aβ in the prodromal phase of AD indicate the importance of intervening early and prelude an exciting opportunity: by focusing on mechanisms related to initial propagation of pathology, disease progression may be halted in the earliest stage, prior to irreversible damage has affected the brain. Autopsy data indicated that the locus coeruleus (LC) is one of the first regions affected by tau: by age 40, tau aggregation in the LC can be detected in 80% of the individuals, prior to neocortical Aβ or tau. At age 50, almost 50% of the individuals harbor tau pathology in the transentorhinal cortex (TEC), suggesting that tau has progressed from the LC to the TEC. The scientific premise supporting the current study emerges from animal and our cerebrospinal fluid (CSF) work, demonstrating that elevated metabolism of the LC may be driving tau hyperphosphorylation, and propagation to distant, connected regions, and triggering cognitive decline. The overall goal of this proposal is to examine LC metabolism and its relation to progression of tau across all stages of the AD continuum, and to model connectivity as mechanism related to progression of tau and cognitive decline. To achieve this, we will resolve two methodological barriers that so far hampered human in vivo assessment of these relationships: 1) measuring LC metabolism while taking into account the resolution of 18F-Fluorodeoxy-glucose PET and 2) identify tracts connecting the LC to the TEC among many crossing brainstem fibers. Combining these state-of- the-art novel methods with longitudinal data of Aβ, tau (PET and CSF) and cognition in two NIA-funded, rich multi-modal longitudinal datasets, the Harvard Aging Brain Study and the Alzheimer Disease Neuroimaging Initiative, will allow us to examine the following aims: Aim 1) To examine the evolution of LC metabolism as a function of Ab/tau stages or diagnostic groups, and its relationship to tau accrual over time; Aim 2A) To identify and validate tracts connecting the LC to the TEC in a consistent way across both cohorts; and examine LC-TEC tract integrity across the AD continuum; and Aim 2B) To model the successive mediation by lower LC- TEC connectivity and tau accrual on the relationship between LC metabolism and cognitive decline. Together, these aims improve our understanding of the mechanistic underpinnings of initial tau propagation, as well as its relevance for cognition. The proposed research is innovative and can have a substantial impact on our understanding of the pathophysiology of AD, and can also result in a significant breakthrough for the field by shifting detection to earlier time points and providing new targets or strategies for therapeutic approaches administered early in the disease trajectory, when brain damage is not yet extensive.