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Depression and accelerated brain aging: A PET imaging study

抑郁症和大脑加速老化：PET 成像研究

基本信息

批准号：
9817103
负责人：
Irina Esterlis
金额：
$ 110.37万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-23 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9817103
关键词：
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 (Brain)Human Impaired cognition Individual Interview Laboratories Lead 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 Short-Term Memory Signaling Protein Structure Synapses Synaptic Transmission Synaptic Vesicles Synaptic plasticity Vesicle Work age related aged aging brain base cognitive function cognitive process dementia risk density depressive symptoms emotion dysregulation executive function 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

项目摘要

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.

项目总结：正常的衰老通过改变突触传递和