STRESS AND INFLAMMATION IN THE PATHOPHYSIOLOGY OF LATE-LIFE DEPRESSION

描述（由申请人提供）：晚年抑郁症（LLD）是全球范围内日益重要的致残和死亡原因。临床研究已经对LLD的现象学和治疗反应的许多方面进行了描述，但LLD的病因尚不清楚。很少有模型产生可测试的假设，但一个新兴的概念是炎症可能有特殊的相关性，特别是在晚年抑郁症中。我们有初步的数据支持，与对照组相比，LLD中炎症细胞因子的增加与海马和杏仁核体积的减少有关。LLD在情景记忆和执行功能方面的神经心理功能也有特异性损害，海马体和杏仁核静息状态功能连通性下降。抗抑郁治疗可改善IL-6水平、神经心理测试和静息状态连通性。在目前的建议中，我们建议招募LLD患者（n = 100）和对照组（n = 50），以表征血管危险因素，免疫功能，脑结构和连通性以及神经心理功能。此外，我们将LLD患者随机分配到10周的SSRI治疗组（n=50）或不治疗组（n=50），并通过外周和中枢细胞因子水平、神经心理测试和大脑静息状态功能连性评估参与者治疗前后的情况。目的1：表征LLD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)与匹配对照组相比，LLD在外周和脑脊液炎症细胞因子、神经心理功能（如执行功能、情景记忆）、海马、杏仁核和前额叶皮质（PFC）结构和功能连通性方面存在异常；b)外周/中枢炎性细胞因子水平将与海马（包括CA2-3、PFC和杏仁核）的体积损失相关；c)抑郁症的累积持续时间与海马（包括CA2-3、杏仁核和pfc）的体积损失相关。目的2：描述脑功能障碍（包括认知障碍）与晚年抑郁症治疗的可逆性及其与炎症的关系。假设2:a)与随机分配到初始未治疗组的受试者相比，随机分配到治疗组的受试者IL-6和IL-10的正常化程度更高，记忆和执行功能的改善更大，静息状态功能连通性的改善也更大；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：神经生物学、抑郁症和炎症之间的假设联系的证明应该促进这种使人衰弱的疾病的治疗策略的发展。

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.