Depression and accelerated brain aging: A PET imaging study

项目摘要：正常衰老通过突触传递和细胞周期的改变缓慢影响大脑。 树突棘形态改变和突触丢失等多种过程的可塑性 蛋白质。严重抑郁障碍(MDD)是世界范围内最普遍和致残性的精神障碍 并与突触信号蛋白的减少有关，如突触前神经递质囊泡- 相关蛋白和突触后结构和功能蛋白。汇聚来自人类的证据 临床和尸检研究以及临床前工作表明，抑郁症可能会加速大脑衰老，因为 表现为神经元萎缩，突触和突触小泡蛋白密度降低，以及小泡 运输和生长，特别是在海马体(HIP)和背外侧前额叶皮质(DlPFC)；以及 因此可能是痴呆症的前兆。在动物和尸检工作中，突触密度的变化 通过对突触小泡蛋白的量化进行了强有力的评估。突触的体内定量研究 最近，随着一种新的放射性配体11C-UCB-J的开发，人类的密度成为可能，它 量化突触囊泡糖蛋白2A(SV2A)的密度，SV2A是突触普遍表达的标志 密度，使用正电子发射断层扫描(PET)成像。在这项研究中，我们将进行第一个已知的 活体人类研究MDD是否可能在25年内(40-65岁)加速突触老化，AS 以及与MDD相关的突触密度变化如何与认知功能和异质性 这种疾病的临床表现。我们的初步数据来自健康成年人的大量标准样本 提示髋部和dlPFC中的突触密度随年龄的增长而系统性下降，这变得更多 随着年龄的增长而发音的。他们进一步揭示了一个更显著的下降 与年龄匹配的健康对照组相比，MDD患者髋部的突触密度和dlPFC。在……里面 在拟议的研究中，我们将采用一种新的加速纵向设计，该设计建立在这些初步结果的基础上 通过检测在体突触密度的变化来评估MDD是否加速突触老化 将髋关节和dlPFC与中老年健康对照组进行比较。我们还将评估 这些脑区的突触密度如何与MDD的内表型和表型表达有关 使用最先进的客观实验室、结构化的临床访谈和神经心理学方法。 拟议的研究结果将提供第一个关于MDD作为潜在的 突触衰老的促进剂以及MDD相关突触密度的变化对临床的影响 表现出这种多方面的紊乱。他们还将为MDD的病理生理模型提供信息 有助于突触老化，并为基于上游机制的新靶点提供了新的见解 旨在缓解大脑加速老化、认知能力下降和痴呆症风险的疗法。

PROJECT SUMMARY: Normal aging slowly affects the brain via alterations in synaptic transmission and plasticity through various processes including changes in dendritic spine morphologies and loss of synaptic proteins. Major depressive disorder (MDD) is the most prevalent and disabling psychiatric disorder worldwide and is associated with reduced synaptic signaling proteins, such as presynaptic neurotransmitter vesicle- associated proteins and postsynaptic structural and functional proteins. Converging evidence from human clinical and postmortem studies, and preclinical work suggests that depression may accelerate brain aging, as evidenced by neuronal atrophy, and reduced synaptic and synaptic vesicle protein densities, and vesicle trafficking and growth, particularly in the hippocampus (HIP) and dorsolateral prefrontal cortex (dlPFC), and may thus represent a prodrome to dementia. In animal and postmortem work, changes in synaptic density have been robustly evaluated via quantification of synaptic vesicle proteins. In vivo quantification of synaptic density in humans was recently made possible with the development of a novel radioligand 11C-UCB-J, which quantifies the density of synaptic vesicle glycoprotein 2A (SV2A), a ubiquitously expressed marker of synaptic density, using positron emission tomography (PET) imaging. In this study, we will conduct the first known in vivo human examination of whether MDD may accelerate synaptic aging over a 25-year span (ages 40-65), as well as how MDD-related changes in synaptic density relate to cognitive functioning and the heterogeneous clinical presentation of this disorder. Our preliminary data from a large normative sample of healthy adults suggest a systematic age-related decline in synaptic density in the HIP and dlPFC, which becomes more pronounced as a function of increasing age. They further reveal a substantially more pronounced decline in synaptic density in the HIP and dlPFC in individuals with MDD compared to age-matched healthy controls. In the proposed study, we will employ a novel accelerated longitudinal design that builds on these initial results by evaluating whether MDD accelerates synaptic aging by examining in vivo changes in synaptic density in the HIP and dlPFC compared to healthy controls across the middle-to-older age spectrum. We will also evaluate how synaptic density in these brain regions relates to the endophenotypic and phenotypic expression of MDD using state-of-the-art objective laboratory, structured clinical interview, and neuropsychological measures. Results of the proposed study will provide the first human in vivo data on the role of MDD as a potential accelerator of synaptic aging, as well as the effect of MDD-related changes in synaptic density on the clinical expression of this multi-faceted disorder. They will also inform pathophysiologic models of how MDD contributes to synaptic aging, and yield new insight into a novel “upstream” mechanism-based target for therapies designed to mitigate accelerated brain aging and risk for cognitive decline and dementia.