STRESS AND INFLAMMATION IN THE PATHOPHYSIOLOGY OF LATE-LIFE DEPRESSION

晚年抑郁症病理生理学中的压力和炎症

• 批准号: 8499914
• 负责人: YVETTE I SHELINE
• 金额: $ 49.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499914
• 关键词: Accounting; Aftercare; Aging; Amygdaloid structure; Animal Model; Antidepressive Agents; Blood Vessels; Brain; Brain region; Cell physiology; Characteristics; Chronic; Clinical; Clinical Research; Data; Development; Disease; Elderly; Episodic memory; Etiology; Exhibits; Exposure to; Functional disorder; Health; Hippocampus (Brain); Human; Immune system; Impaired cognition; Impairment; Inflammation; Inflammatory; Interleukin-10; Interleukin-6; Interneurons; Investigation; Kynurenine; Life; Link; Medical; Memory; Mental Depression; Modeling; Neurobiology; Neuropsychological Tests; Participant; Parvalbumins; Patients; Peripheral; Plasma; Population; Prefrontal Cortex; Prevention strategy; Production; Randomized; Recruitment Activity; Research; Rest; Risk; Risk Factors; Selective Serotonin Reuptake Inhibitor; Serotonin; Stress; Structure; Sulfones; Tryptophan; Waiting Lists; age related; cytokine; depressive symptoms; disability; executive function; frontal lobe; functional improvement; geriatric depression; immune function; improved; inflammatory marker; inhibitory neuron; methionine sulfoxide; mortality; neuropsychological; peripheral blood; public health relevance; treatment response; treatment strategy

DESCRIPTION (provided by applicant): Late life depression (LLD) is an increasingly important cause of disability and mortality worldwide. Clinical studies have characterized many aspects of the phenomenology, and treatment response in LLD, but the etiology of LLD remains unclear. Few models have yielded testable hypotheses, but an emerging concept is that inflammation may have particular relevance, especially in late life depression. We have preliminary data supporting increased inflammatory cytokines in LLD compared with controls that are associated with decreased hippocampus and amygdala volumes. LLD also had specific impairment in neuropsychological function in episodic memory and executive function and decreased hippocampus and amygdala resting state functional connectivity. Antidepressant treatment improved IL-6 levels, neuropsychological testing and resting state connectivity. In the current proposal we propose to recruit patients with LLD (n = 100) and controls (n = 50) matched for vascular risk factors to characterize immune function, brain structure and connectivity and neuropsychological function. Further, we will randomize participants with LLD to 10 weeks of SSRI treatment (n=50) or no treatment (wait list) (n=50), and assess participants pre- and post-treatment with peripheral and central cytokine levels, neuropsychological tests and brain resting state functional connectivity. Aim 1: Characterize neuroanatomical and neuropsychological correlates of abnormal cytokines in LLD. Hypothesis 1: a) Compared with matched controls, LLD will have abnormalities in peripheral and CSF inflammatory cytokines, neuropsychological function (e.g., executive function, episodic memory), hippocampal, amygdala and prefrontal cortex (PFC) structure and functional connectivity; b) Peripheral/central inflammatory cytokine levels will be associated with volume loss in hippocampus, including CA2-3, PFC, and amygdala; and c) Cumulative duration of depression will correlate with volume loss in hippocampus, including CA2-3, amygdala, and PFC. Aim 2: Characterize the reversibility of brain dysfunction, including cognitive impairment, with treatment of late- life depression and its association with inflammation. Hypothesis 2: a) Subjects randomized to treatment will have greater normalization of IL-6 and IL-10, greater improvements in memory and executive function and improvements in resting state functional connectivity compared with those randomized to initial no treatment; b) Improvement in clinical depressive scores will correlate with normalizatio of inflammatory cytokines. Significance: Demonstration of hypothesized links between neurobiology, depression and inflammation should augment development of treatment strategies for this debilitating disorder.

描述（由申请人提供）：晚年抑郁症 (LLD) 是全世界残疾和死亡的一个日益重要的原因。临床研究已经描述了 LLD 的现象学和治疗反应的许多方面，但 LLD 的病因仍不清楚。很少有模型能够得出可检验的假设，但一个新兴的概念是炎症可能具有特殊的相关性，尤其是在晚年抑郁症中。我们有初步数据支持 LLD 中炎症细胞因子的增加与海马体和杏仁核体积减少相关。 LLD 还对情景记忆和执行功能的神经心理功能造成特定损害，并降低海马体和杏仁核静息态功能连接。抗抑郁治疗改善了 IL-6 水平、神经心理学测试和静息态连通性。在当前的提案中，我们建议招募与血管危险因素相匹配的 LLD 患者 (n = 100) 和对照患者 (n = 50)，以表征免疫功能、大脑结构和连通性以及神经心理功能。此外，我们将 LLD 参与者随机分为接受 10 周 SSRI 治疗的参与者 (n=50) 或不治疗（等待名单）(n=50)，并评估参与者治疗前和治疗后的外周和中枢细胞因子水平、神经心理学测试和大脑静息状态功能连接。目标 1：表征 LLD 中异常细胞因子的神经解剖学和神经心理学相关性。假设1：a）与匹配对照相比，LLD的外周和脑脊液炎症细胞因子、神经心理功能（例如执行功能、情景记忆）、海马、杏仁核和前额皮质（PFC）结构和功能连接出现异常； b) 外周/中枢炎症细胞因子水平与海马体积减少相关，包括 CA2-3、PFC 和杏仁核； c) 抑郁的累积持续时间将与海马体体积减少相关，包括 CA2-3、杏仁核和 PFC。目标 2：通过治疗晚年抑郁症及其与炎症的关系来表征脑功能障碍（包括认知障碍）的可逆性。假设 2：a) 与随机接受初始不治疗的受试者相比，随机接受治疗的受试者的 IL-6 和 IL-10 的正常化程度更高，记忆和执行功能有更大的改善，静息状态功能连接也有改善； b) 临床抑郁评分的改善与炎症细胞因子的正常化相关。意义：证明神经生物学、抑郁症和炎症之间的假设联系应该会促进这种使人衰弱的疾病的治疗策略的发展。