Depression and accelerated brain aging: A PET imaging study

抑郁症和大脑加速老化：PET 成像研究

• 批准号: 10623139
• 负责人: Irina Esterlis
• 金额: $ 106.15万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623139
• 关键词: Acceleration; Adult; Affect; Age; Age Years; Age-associated memory impairment; Aging; Animals; Atrophic; Attention; Autopsy; Biological Markers; Brain; Brain region; Chronic; Chronology; Clinical; Clinical Research; Cognition; Consensus; Data; Dementia; Dendritic Spines; Depressed mood; Development; Disease; Elderly; Energy Metabolism; Glycoproteins; Growth; Hippocampus; Human; Impaired cognition; Individual; Interview; Laboratories; Learning; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Mediating; Memory; Mental Depression; Mental disorders; Modeling; Molecular; Molecular Target; Morphology; Neurons; Neuropsychology; Neurotransmitters; Phenotype; Population; Positron-Emission Tomography; Prefrontal Cortex; Prevention; Process; Proteins; Risk; Role; Sampling; Severities; Signaling Protein; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Technology; Vesicle; Work; age related; aged; aging brain; biomarker identification; cognitive function; cognitive process; dementia risk; density; depressive symptoms; emotion dysregulation; endophenotype; executive function; human old age (65+); imaging study; in vivo; insight; long term memory; longitudinal design; neurochemistry; normal aging; novel; postsynaptic; pre-clinical; preclinical study; presynaptic; processing speed; radioligand; receptor; synaptogenesis; targeted treatment; therapy design; trafficking

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.

项目摘要：正常衰老会通过改变突触传播和 通过各种过程的可塑性，包括树突状脊柱形态的变化和突触的丧失 蛋白质。重度抑郁症（MDD）是全球最普遍，最致命的精神障碍 并且与降低的合成信号蛋白有关，例如突触前神经递质囊泡 - 相关蛋白质以及突触后结构和功能蛋白。来自人类的证据 临床和验尸研究以及临床前研究表明，抑郁症可能会加速大脑衰老，因为 神经元萎缩证明，突触和突触囊泡蛋白密度和囊泡降低 贩运和增长，特别是在海马（髋关节）和背外侧前额叶皮层（DLPFC）和 因此，可以代表痴呆症的前途。在动物和死后工作中，突触密度的变化 通过定量突触囊泡蛋白来对其进行了可靠的评估。体内突触定量 最近，随着新型的放射性物体11C-UCB-J的发展，人类的密度成为可能，该密度成为可能 量化突触囊泡糖蛋白2a（SV2A）的密度，这是一种无处不在的突触的标志物 密度，使用二极化发射断层扫描（PET）成像。在这项研究中，我们将进行第一个已知的 人类对MDD是否可以在25年跨度（40-65岁）中加速合成老化的体内检查 以及与MDD相关的突触密度变化与认知功能和异质性的变化 这种疾病的临床表现。我们来自大型健康成年人的大量正常样本的初步数据 建议在髋关节和DLPFC中系统地与年龄相关的突触密度下降，这变得更加 发音是年龄增长的函数。他们进一步揭示了明显的下降 与年龄匹配的健康对照相比，MDD患者的髋关节和DLPFC的突触密度。在 拟议的研究，我们将采用一种新颖的加速纵向设计，以这些初始结果为基础 评估MDD是否通过检查体内合成密度变化的合成密度变化来加速合成衰老 与中等年龄较大的年龄频谱中的健康对照相比，髋关节和DLPFC。我们还将评估 这些大脑区域的突触密度如何与MDD的内苯酚和苯并表达相关 使用最先进的目标实验室，结构化的临床访谈和神经心理学测量。 拟议的研究的结果将提供有关MDD作用的第一个人体体内数据 合成衰老的加速器，以及与MDD相关的合成密度变化对临床的影响 这种多面疾病的表达。他们还将告知病理生理模型MDD 有助于综合衰老，并为基于新型的“上游”机制的目标产生新的见解 旨在减轻加速脑衰老的疗法和认知能力下降和痴呆症的风险。