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

摘要：阿尔茨海默病（AD）的神经病理学特征是β-淀粉样蛋白的积累 （Aβ）和tau蛋白，其各自在疾病进展期间具有其自身的典型拓扑结构。的事实 病理进展的这种解剖模式发生在解剖学上相连的沿着区域， 病理通过连接传播。最近针对Aβ的治疗结果令人失望， AD的前驱期表明早期干预的重要性，并预示着一个令人兴奋的机会： 通过关注与病理学最初传播相关的机制， 在不可逆损伤之前的最早阶段已经影响到大脑。尸检数据显示， 蓝斑（LC）是受tau影响的第一个区域之一：到40岁时，可以检测到LC中的tau聚集， 80%的个体，在新皮质Aβ或tau之前。在50岁时，几乎50%的个体携带tau蛋白 在经内嗅皮质（TEC）中的病理学，表明tau已经从LC进展到TEC。的 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， 这表明LC代谢的升高可能驱动tau蛋白过度磷酸化， 到遥远的相连区域，引发认知能力下降本提案的总体目标是审查 LC代谢及其与AD连续体所有阶段中tau进展的关系， 连接性作为与tau蛋白和认知衰退进展相关的机制。为了实现这一目标，我们将致力于 迄今为止，有两个方法学障碍阻碍了对这些关系的人体体内评估：1） 测量LC代谢，同时考虑18 F-氟脱氧葡萄糖PET的分辨率，以及2） 在许多交叉的脑干纤维中识别连接LC到TEC的束。结合这些国家- 最先进的新方法与纵向数据的Aβ，tau（PET和CSF）和认知在两个国家情报局资助，丰富的 多模态纵向数据集，哈佛老化脑研究和阿尔茨海默病神经成像 主动，将使我们能够检查以下目标：目标1）检查LC代谢的演变， Ab/tau分期或诊断组的功能，及其与tau随时间增加的关系;目的2A） 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 目的2B）通过较低的LC-100来模拟连续介导的连续介导。 TEC连接性和tau蛋白累积在LC代谢和认知功能下降之间的关系。在一起， 这些目标提高了我们对初始tau传播的机制基础的理解，以及 它与认知的相关性。拟议的研究是创新的，可以产生重大影响，我们的 了解AD的病理生理学，也可以导致该领域的重大突破， 将检测转移到更早的时间点，并为治疗方法提供新的靶点或策略 在疾病发展的早期，当脑损伤还不广泛时，

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.