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

社会脱节（SDC）和自杀死亡是主要的公共卫生问题， 人口老龄化。SDC是老年人自杀意念、企图和死亡的最强风险因素之一。 成年人，是这一人群自杀预防工作的一个可修改的目标。在收集证据的同时 已经建立了SDC和晚年自杀风险之间的联系， 这一关联仍然未知。因此，我们对如何进行最佳干预以减轻 SDC对老年人自杀风险的不利影响有限。为了弥补这一差距，我们建议 进行了第一个潜在神经机制的体内分子成像研究-皮质边缘突触 密度-这可能介导SDC和晚年自杀风险之间的联系。鉴于较高的患病率， 在老年男性自杀死亡率高于女性的情况下，我们还将研究性别是否会调节这种关联。 来自人体磁共振成像、尸检研究和临床前工作的证据 提示SDC和自杀倾向的大脑改变，有强有力的证据表明较低的皮质边缘突触 密度的在SDC的动物模型中，社会化似乎可以逆转其中一些突触损失。这些 研究还观察到，在旨在逆转SDC的干预中，突触变化存在性别差异， 相关的突触丢失因此，进行人体内研究以评估分子机制是至关重要的 这可能会给SDC老年人带来自杀风险，以确定谁的风险最大，以及如何 减轻自杀对老年人、他们的家庭和整个社区的负担。体内定量 用放射性配体11 C-UCB-J可以定量人的突触密度， 囊泡糖蛋白2A（SV 2A），一种普遍表达的突触密度标记物，使用正电子发射 断层摄影（PET）成像。我们从不同老年人样本中获得的初步数据证实了临床前 SDC中皮质边缘突触密度较低的发现表明存在性别特异性差异。拟议 在这项研究中，我们将招募一个跨诊断队列的老年人提出了全方位的SDC和评估 较低的皮质边缘突触密度是否介导了SDC和纵向轨迹之间的关系， 以一种性别特异性的方式增加晚年自杀的风险。我们将采用一种新颖的数据驱动方法来建模 晚年自杀风险的主要轨迹，其中将包括自杀的措施 抑郁 和死亡意念， 症状，个人和自我价值的丧失，执行控制，以及对生活意义的感知。 这项研究的结果将提供第一个关于突触密度改变作用的人体体内数据。 作为一种假定的神经机制，将SDC与晚年自杀风险联系起来。它们还将为发展提供信息， 测试靶向干预以增强突触发生（例如，药物如氯胺酮或 心理社会干预措施，如同伴支持），以及促进社会联系的公共政策 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.