Role of Systemic Inflammation in Cognitive Decline: Rheumatoid Arthritis as a Prototype

项目摘要/摘要 与年龄相关的全身炎症负担的增加是一种关键因素和潜在的治疗目标 阿尔茨海默病(AD)和其他与年龄相关的痴呆症。类风湿性关节炎(RA)是一种自身免疫性高 炎症性疾病是了解慢性炎症和 认知衰退中的自身免疫和抗风湿治疗的调节作用。纵向研究 缺乏RA等慢性炎症性疾病的痴呆症风险和时间的大小， 导致了巨大的知识鸿沟。 慢性炎症是痴呆症发病的先兆。此外，越来越多的证据表明， 抗风湿药物对阿尔茨海默病的影响。我们建议利用现有的类风湿性关节炎患者队列数据 和不含RA的配对比较器(R01 AR046849)，以量化和比较RA与 非RA参与者，并以RA为研究对象，确定慢性全身性炎症在认知衰退中的作用 原型。我们将确定慢性全身炎症和抗风湿治疗对 RA患者的痴呆症，调整了重要的混杂因素(年龄、性别、教育程度、社会经济地位、 吸烟、肥胖、心血管疾病、抑郁症)。此外，利用梅奥诊所的老龄化研究 参考资料(U01 AG006786)，我们将定义患者认知功能和神经影像标志物的变化 根据类风湿关节炎的炎症程度和使用抗风湿治疗。 成功完成拟议的一系列研究将是了解 慢性暴露于全身炎症会对认知产生不良影响，以及是否严格控制全身炎症 抗风湿治疗的炎症有保护作用。我们现有的队伍提供了一个难得的机会 以有效地解决这一知识鸿沟。潜在的下游影响是显著的，包括新的战略 预防和处理类风湿性关节炎患者的痴呆，并为未来的研究提供新的见解 在普通人群中预防痴呆症。

PROJECT SUMMARY/ABSTRACT Age-related increase in the burden of systemic inflammation is a key player and potential treatment target in Alzheimer’s disease (AD) and other age-related dementias. Rheumatoid arthritis (RA) is an autoimmune hyper- inflammatory disease and an excellent model for understanding the role of chronic inflammation and autoimmunity in cognitive decline and the modulating effects of anti-rheumatic therapies. Longitudinal studies on the magnitude of the risk and timing of dementia in chronic inflammatory conditions such as RA are lacking, resulting in a substantial knowledge gap. Chronic inflammation precedes the onset of dementia. Furthermore, growing evidence suggests a protective effect of anti-rheumatic medications on AD. We propose to utilize data from existing cohorts of patients with RA and matched comparators without RA (R01 AR046849) to quantify and compare the risk of dementia in RA vs. non-RA participants and to define the role of chronic systemic inflammation in cognitive decline using RA as a prototype. We will determine the impact of chronic systemic inflammation and anti-rheumatic treatments on dementia in RA patients, adjusting for important confounders (age, sex, education, socio-economic status, smoking, obesity, cardiovascular disease, depression). Additionally, using the Mayo Clinic Study of Aging resources (U01 AG006786), we will define change of cognitive function and neuroimaging markers in patients with RA according to the level of inflammation and use of anti-rheumatic treatments. Successful completion of the proposed series of studies will be a key step towards understanding whether chronic exposure to systemic inflammation has adverse cognitive effects and whether tight control of systemic inflammation with anti-rheumatic treatments has protective effects. Our existing cohorts offer a rare opportunity to efficiently address this knowledge gap. Potential downstream effects are significant, including new strategies for prevention and management of dementia in patients with RA and new insights for future studies on prevention of dementia in the general population.