Depression and accelerated brain aging: A PET imaging study

项目概述：正常衰老通过突触传递的改变缓慢影响大脑， 可塑性通过各种过程，包括树突棘形态的变化和突触的损失， proteins.重性抑郁障碍（MDD）是世界范围内最常见的精神疾病 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。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， 表现为神经元萎缩，突触和突触囊泡蛋白密度降低， 运输和生长，特别是在海马（HIP）和背外侧前额叶皮层（dlPFC），和 因此可能是痴呆的前驱症状。在动物和死后的研究中，突触密度的变化 已经通过突触囊泡蛋白的定量进行了稳健的评估。突触的体内定量 最近，随着新型放射性配体11 C-UCB-J的开发， 量化突触囊泡糖蛋白2A（SV 2A）的密度，SV 2A是突触囊泡糖蛋白2A的普遍表达标志物， 密度，使用正电子发射断层扫描（PET）成像。在这项研究中，我们将进行第一次已知的， 在25年的时间跨度内（40-65岁），MDD是否可能加速突触老化的体内人体检查， 以及MDD相关的突触密度变化如何与认知功能和异质性相关。 这种疾病的临床表现。我们的初步数据来自一个健康成年人的大样本 表明HIP和dlPFC中突触密度的系统性年龄相关性下降， 随着年龄的增长而明显。他们进一步揭示了一个更明显的下降， 与年龄匹配的健康对照相比，MDD患者的HIP和dlPFC中的突触密度。在 建议的研究，我们将采用一种新的加速纵向设计，建立在这些初步结果， 通过检查突触密度的体内变化来评估MDD是否加速突触老化。 HIP和dlPFC与健康对照组在中老年人群中的比较。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相关 使用最先进的客观实验室、结构化临床访谈和神经心理学测量。 拟议研究的结果将提供关于MDD作为潜在的 突触老化的加速剂，以及MDD相关的突触密度变化对临床 这种多方面的疾病的表现。他们还将告知病理生理模型， 有助于突触老化，并产生新的洞察到一个新的“上游”机制为基础的目标， 旨在缓解大脑加速老化和认知能力下降和痴呆症风险的治疗。

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.