Role of synaptic density in mediating the relation between social disconnection and late-life suicide risk

突触密度在调节社会脱节与晚年自杀风险之间关系中的作用

• 批准号: 10598338
• 负责人: Irina Esterlis
• 金额: $ 90.45万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598338
• 关键词: Address; Adult; Adverse effects; Affect; Age; Amygdaloid structure; Animal Model; Animals; Anterior; Autopsy; Brain; Brain region; Cessation of life; Communities; Data; Decision Making; Development; Diagnostic; Elderly; Emotional; Family; Feeling suicidal; Fostering; Glycoproteins; Health; High Prevalence; Hippocampus; Human; Image; Individual; Intervention; Ketamine; Left; Life; Link; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Molecular; Neurocognitive; Pharmaceutical Preparations; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Prevention strategy; Property; Public Health; Public Policy; Reporting; Risk; Risk Factors; Role; Sampling; Severities; Sex Differences; Social isolation; Social outcome; Socialization; Suicide; Suicide prevention; Symptoms; Synapses; Synaptic Vesicles; Testing; Woman; Work; age group; aged; aging population; brain tissue; clinically significant; cognitive function; cohort; density; depressive symptoms; environmental enrichment for laboratory animals; executive function; ideation; imaging study; in vivo; male; men; molecular imaging; molecular marker; multimodality; neurobiological mechanism; neuroimaging; neuromechanism; novel; older men; peer support; pre-clinical; psychologic; psychosocial; radioligand; recruit; sex; social; social engagement; suicidal; suicidal morbidity; suicidal risk; suicide rate; synaptogenesis; therapy design

PROJECT SUMMARY: Social disconnection (SDC) and suicide deaths are major public health concerns for the aging population. SDC is one of the strongest risk factors of suicidal ideation, attempts, and deaths in older adults, and is a modifiable target for suicide prevention efforts in this population. While accumulating evidence has established an association between SDC and late-life suicide risk, the neural mechanisms that underlie this association remain unknown. Consequently, our understanding of how to optimally intervene to mitigate the adverse effects of SDC on suicide risk in older adults is limited. To address this gap, we propose to conduct the first in vivo molecular imaging study of a potential neural mechanism – corticolimbic synaptic density – that may mediate the link between SDC and late-life suicide risk. Given a higher prevalence of suicide death in older men than women, we will also examine whether sex moderates this association. Converging evidence from human magnetic resonance imaging and postmortem studies and preclinical work suggests brain alterations in SDC and suicidality, with robust evidence implicating lower corticolimbic synaptic density. In animal models of SDC, socialization appears to reverse some of these synaptic losses. These studies have also observed sex differences in synaptic changes in interventions designed to reverse SDC- related synaptic losses. Thus, it is critical to conduct in vivo human studies to evaluate molecular mechanisms that may confer risk for suicide in older adults with SDC in order to identify who is at greatest risk and how to mitigate burden of suicide to older adults, their families, and the community at large. In vivo quantification of synaptic density in humans is possible with the 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. Our preliminary data from a diverse sample of older adults confirm preclinical findings of lower corticolimbic synaptic density in SDC and suggest sex-specific differences. In the proposed study, we will recruit a transdiagnostic cohort of older adults presenting with the full range of SDC and evaluate whether lower corticolimbic synaptic density mediates the relation between SDC and longitudinal trajectories of late-life suicide risk in a sex-specific manner. We will employ a novel, data-driven approach to model predominant trajectories of late-life suicide risk, which will include measures of suicide depressive and death ideation, symptoms, loss of personal and self-worth, executive control, and perceived meaning in life. Results of the proposed study will provide the first human in vivo data on the role of synaptic density alterations as a putative neural mechanism linking SDC to late-life suicide risk. They will also inform the development and testing of targeted interventions to enhance synaptogenesis (e.g., medications such as ketamine or psychosocial interventions such as peer support), as well as public policies to promote social connection among older adults who may suffer from illness or other issues that lead to SDC.

项目摘要：社会断开（SDC）和自杀死亡是主要的公共卫生问题 人口老龄化。 SDC是自杀想法，尝试和死亡的强大风险因素之一 成人，是该人群中预防自杀式工作的可修改目标。同时积累证据 已经建立了SDC与后期自杀风险之间的关联，这是基于的神经机制 该关联仍然未知。因此，我们对如何最佳干预以减轻的理解 SDC对老年人自杀风险的不利影响受到限制。为了解决这个差距，我们建议 进行潜在神经力学的第一个体内分子成像研究 - 皮质脂质突触 密度 - 可能会介导SDC与后期自杀风险之间的联系。鉴于更高的患病率 比男性年龄较大的男性自杀死亡，我们还将检查性别是否适应这种关联。 人类磁共振成像和验尸研究和临床前工作的融合证据 提示SDC和自杀性的大脑改变，具有强大的证据暗示性较低的皮质脂质突触 密度。在SDC的动物模型中，社会化似乎扭转了其中一些合成损失。这些 研究还观察到了旨在逆转SDC-的干预措施的突触变化的性别差异 相关的合成损失。这一点至关重要的是进行体内人类研究以评估分子机制 这可能会召集患有SDC老年人自杀的风险，以确定谁处于最大风险以及如何 减轻对老年人，家庭和整个社区的自杀燃烧。体内定量 radioligand 11c-ucb-j可以在人类中的突触密度，这量化了突触的密度 囊泡糖蛋白2a（SV2A）是一种普遍表达的突触密度标记，使用极性发射 断层扫描（PET）成像。我们来自老年人潜水员样本的初步数据证实了临床前 SDC中较低的皮质脂质突触密度的发现，并提示性别特异性差异。在提议中 研究，我们将招募一个呈现全范围SDC的老年人的经诊断队列并评估 较低的皮层突触密度是否介导了SDC与纵向轨迹之间的关系 晚期自杀的风险以特定的性别方式。我们将采用一种新颖的，数据驱动的方法来建模 晚期自杀风险的主要轨迹，其中包括自杀的测量 抑郁 和死亡的想法， 症状，个人和自我价值的丧失，执行控制以及生活中感知的意义。 拟议的研究的结果将提供有关突触密度改变作用的第一个人体体内数据 作为一种推定的神经力学，将SDC与后期自杀风险联系起来。他们还将告知开发以及 测试靶向干预措施以增强突触发生（例如，氯胺酮或 社会心理干预措施，例如同伴支持）以及促进社会联系的公共政策 在可能遭受疾病或其他导致SDC的问题的老年人中。