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

项目摘要：社会脱节和自杀死亡是 老龄化的人口。SDC是老年人自杀念头、企图和死亡的最强烈的危险因素之一 在这一人群中，它是自杀预防工作的一个可修改的目标。在积累证据的同时 已经建立了SDC和晚年自杀风险之间的联系，这是潜在的神经机制 这种联系仍不清楚。因此，我们对如何以最佳方式干预以缓解 SDC对老年人自杀风险的不良影响是有限的。为了解决这一差距，我们建议 首次对一种潜在的神经机制--皮质边缘突触进行体内分子成像研究 密度--这可能在SDC和晚年自杀风险之间起到中介作用。鉴于更高的流行率 在男性自杀死亡年龄大于女性的情况下，我们还将检查性行为是否缓和了这种联系。 来自人类磁共振成像、尸检研究和临床前工作的聚合证据 提示SDC和自杀倾向的脑部改变，有强有力的证据表明下皮质边缘突触 密度。在SDC的动物模型中，社会化似乎可以逆转其中一些突触丢失。这些 研究还观察到，在旨在逆转SDC的干预措施中，突触变化的性别差异。 相关的突触丢失。因此，进行活体人体研究以评估分子机制是至关重要的。 这可能会增加患有SDC的老年人自杀的风险，以便确定谁处于最大的风险以及如何 减轻老年人、他们的家人和整个社区的自杀负担。在体定量测定 放射性配基11C-UCB-J可以量化突触的密度，从而使人类的突触密度成为可能 囊泡糖蛋白2A(SV2A)是突触密度的一个普遍表达的标志，用正电子发射 断层扫描(PET)成像。我们从不同的老年人样本中获得的初步数据证实了临床前 SDC的皮质边缘突触密度较低，提示性别差异。在建议的 研究中，我们将招募一组表现出各种SDC的老年人的跨诊断队列，并评估 较低的皮质边缘突触密度是否在SDC与轴突轨迹之间的关系中起中介作用 晚年自杀风险与性别有关。我们将使用一种新颖的、数据驱动的方法来建模 晚年自杀风险的主要轨迹，其中将包括自杀措施 抑郁 和死亡的想法， 症状，个人和自我价值的丧失，执行控制，以及对生活的感知意义。 这项拟议的研究结果将提供第一个关于突触密度改变的作用的活体人类数据 作为一种假定的神经机制，将SDC与晚年自杀风险联系起来。他们还将通报事态的发展和 测试促进突触发生的有针对性的干预措施(例如，氯胺酮或 心理社会干预，如同伴支持)，以及促进社会联系的公共政策 对于可能患有疾病或其他导致SDC的问题的老年人。

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.