Phenotype Predictors of Cognitive Outcomes in Geriatric Depression

在R01MH108578的这一竞争性更新中，我们正在寻求将最初研究的结果扩展到 关注压力对老年抑郁症(LLD)的纵向情绪和认知结果的影响 研究应激对LLD患者大脑结构和功能的影响。严重或持续的压力源可导致 行为和情绪变化的数量，包括焦虑，烦躁不安，睡眠障碍，食欲改变， 以及从社交和愉快的活动中退出。这些与压力相关的后果尤其是 在考虑治疗后LLD的纵向结果时，这一点尤为突出。它们可能会被一个人的 长期存在的对压力的不适应模式，体现在神经质的结构中，我们 已被证明与糟糕的情绪和认知LLD结果有关。此外，Andreescu et al.(2019年) 引入了一个抑郁复发的模型，该模型结合了体内平衡不平衡假说， 这表明，在老年缓解性抑郁症中，神经网络处于脆弱的动态平衡状态，即 受到压力的威胁。在LLD结果的压力方面特别重要的网络是默认的 模式网络(DMN)、显著网络(SN)和执行控制网络(ECN)。 老年抑郁症的神经生物学(NBOLD)研究开始招募老年抑郁症和从不- 抑郁对照在2013年，登记了132名抑郁对照和44名对照，目前跟踪了77名抑郁和 22个对照。受试者在情绪、认知、个性和压力方面都有良好的特征(包括 在当前COVID大流行期间获得的具体措施)。它非常适合于研究压力对 纵向情绪和认知结果。对于续签，我们将遵循现有的科目，并招募75名新的 受试者，将接受长达5年的年度认知测试、压力测量和基线跟踪 和两年的脑功能磁共振扫描。在本申请中提供的初步数据中，我们显示： 1)在抑郁的老年人中，与4年内出现认知能力下降/痴呆的人相比， 保持认知正常，两年内神经质的减少和责任心的增加更大。 2)超过两年的压力恶化与两年来海马体体积的减少有关，并且是 与大脑关键区域功能连接的变化有关。 3)在复杂的统计建模中，神经质的变化和 最近经历的压力源与认知结果有关。 在这次相互竞争的更新中，我们将审查以下具体目标： 1.研究应激源(通过各种测量获得)和神经质对纵向情绪和精神质的影响 有严重抑郁障碍病史的老年人的认知结果。 2.研究应激和神经质对有MDD病史的老年人脑结构和功能的影响。 3.用纵向多变量统计模型探讨AIMS 1和AIMS 2中变量间的关系。

In this competing renewal of R01MH108578, we are seeking to extend findings from the initial study to focus on effects of stress in longitudinal mood and cognitive outcomes of late-life depression (LLD) and to examine stress effects on brain structure and function in LLD. Severe or persistent stressors can result in a number of behavioral and mood changes, including anxiety, dysphoric mood, sleep disruption, altered appetite, and withdrawal from social and pleasurable activities. These stress-related consequences are particularly salient when considering longitudinal outcomes of treated LLD. They may be compounded by an individual's longstanding maladaptive patterns of response to stress, embodied in the construct of neuroticism, which we have shown to be related to poor mood and cognitive LLD outcomes. Moreover, Andreescu et al. (2019) introduced a model of depression recurrence that incorporates the homeostatic disequilibrium hypothesis, which proposes that in geriatric remitted depression, neural networks are in fragile homeostasis that is threatened by stress exposure. Networks of particular importance in stress of LLD outcome are the Default Mode Network (DMN), Salience Network (SN) and Executive Control Network (ECN). The Neurobiology of Late Life Depression (NBOLD) study began enrolling older depressed and never- depressed controls in 2013, enrolling 132 depressed and 44 controls, and currently follows 77 depressed and 22 controls. Subjects are well characterized in terms of mood, cognition, personality and stress (including specific measures obtained during the present COVID pandemic). It is well suited to examine stress effects on longitudinal mood and cognitive outcomes. For the renewal, we will follow current subjects and recruit 75 new subjects, who will be followed for up to 5 years with annual cognitive testing, stress measures and baseline and two-year brain fMRI scan. In preliminary data presented in this application, we show that: 1) In depressed elders, compared with those who developed cognitive decline/dementia in 4 years, those who remained cognitively normal had greater 2-year decrease in neuroticism and increase in Conscientiousness. 2) Worsening in stress over two years is associated with two-year decrease in hippocampal volume and is associated with changes in functional connectivity of key brain regions.. 3) In complex statistical modeling, interactions of changes in neuroticism and changes in the number of stressors recently experienced are associated with cognitive outcome. In this competing renewal, we will examine the following specific aims: 1. To study effects of stressors (obtained on a variety of measures) and neuroticism on longitudinal mood and cognitive outcomes in older adults with history of major depressive disorder (MDD). 2. To study effects of stress and neuroticism on brain structure and function in older adults with MDD history. 3. To explore relationships among variables in Aims 1 and 2 with longitudinal multivariable statistical models.