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）：晚期抑郁症（LLD）是全球残疾和死亡率的越来越重要的原因。临床研究表征了现象学的许多方面和LLD的治疗反应，但LLD的病因尚不清楚。很少有模型提出可检验的假设，但是新出现的概念是炎症可能具有特殊的意义，尤其是在后期抑郁症中。与与海马和杏仁核降低有关的对照组相比，我们有初步数据支持LLD中炎症细胞因子增加的增加。 LLD在情节记忆和执行功能中的神经心理功能方面还具有特定的损害，并降低了海马和杏仁核静息状态功能连通性。抗抑郁药治疗改善了IL-6水平，神经心理学测试和静止状态连通性。在当前的建议中，我们建议招募LLD患者（n = 100）和对照组（n = 50）的血管风险因素，以表征免疫功能，大脑结构，连通性和神经心理学功能。此外，我们将将LLD的参与者随机为10周的SSRI治疗（n = 50）或无治疗（等待名单）（n = 50），并评估参与者使用周围和中央细胞因子水平，神经心理学测试，神经心理学测试以及脑静止状态功能连接的治疗前和治疗后的参与者。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）与匹配的对照相比，LLD在周围和CSF炎症细胞因子，神经心理学功能（例如执行功能，情节记忆），海马，杏仁核和前额叶皮层（PFC）结构和功能连接性方面具有异常； b）外周/中央炎症细胞因子水平将与海马的体积损失有关，包括CA2-3，PFC和杏仁核； c）抑郁症的累积持续时间将与海马的体积损失相关，包括CA2-3，杏仁核和PFC。 AIM 2：表征脑功能障碍的可逆性，包括认知障碍，治疗后期抑郁及其与炎症的关联。假设2：a）随机进行治疗的受试者将具有更大的IL-6和IL-10的归一化，与随机分配到初始无治疗的人相比，记忆和执行功能的改善和静止状态功能连接的改善以及静止状态功能连接的改善； b）临床抑郁评分的改善将与炎症细胞因子的施加量表有关。意义：神经生物学，抑郁和炎症之间的假设联系应增强这种令人衰弱的疾病的治疗策略。