Cell-free DNA as a marker of progression in Alzheimer's dementia and its role in chronic inflammation

项目摘要/总结： 轻度认知障碍（MCI）定义为在一个或多个领域中具有受损的认知， 日常生活活动的限制，并可能代表一个时间点，在这个时间点上， (AD)可以实现。然而，从MCI到AD的进展率存在显著差异; 因此，非侵入性地鉴定处于疾病进展最高风险的个体是至关重要的。一个提议的 疾病进展的标志物是细胞死亡过程中释放的游离DNA（cf-DNA）。测量 血清cf-DNA传达了有关细胞死亡机制的信息，可以帮助我们更好地了解能量 死亡细胞的变化。确定cf-DNA和免疫系统激活之间的联系， 我们可以更好地认识导致MCI和AD慢性炎症的因素。本研究假设 MCI患者中cf-DNA水平的增加与更快的AD进展速率相关， cf-DNA通过激活核因子κ B（NF-κ B）导致AD相关慢性炎症， kB）途径。数字PCR将用于测量MCI个体和正常个体血清中的cf-DNA水平 将研究认知以及与认知下降率的关联（目标1）。分化的人神经元 将评价用来自MCI和正常认知个体的纯化cf-DNA处理的细胞系， 炎性细胞因子产生、NF-κ B信号传导激活和细胞死亡的变化（Aim 2）。这 创新的研究有可能确定重要的免疫信号通路，以进一步研究 在AD的背景下，可以通过利用cf-DNA作为与AD发生率相关的标志物来直接影响患者护理。 MCI患者的疾病进展。

PROJECT ABSTRACT/SUMMARY: Mild cognitive impairment (MCI) is defined as having impaired cognition in one or more domains with minimal limitations to daily life activities and may represent a timepoint at which interventions for Alzheimer’s disease (AD) can be implemented. However, there is significant variability in rates of progression from MCI to AD; therefore, it is critical to non-invasively identify individuals at highest risk of disease progression. One proposed marker of disease progression is cell-free DNA (cf-DNA), which is released from cell death processes. Measuring serum cf-DNA conveys information about cell death mechanisms that can help us better understand energy changes in the dying cells. Determining the connections between cf-DNA and immune system activation allows us to better recognize factors that contribute to chronic inflammation in MCI and AD. This study hypothesizes that increased cf-DNA levels in individuals with MCI are associated with faster rates of progression to AD, and that cf-DNA contributes to AD-associated chronic inflammation via activation of the nuclear factor kappa-B (NF- kB) pathway. Digital PCR will be used to measure cf-DNA levels in serum of individuals with MCI and normal cognition and associations with rates of cognitive decline will be studied (Aim 1). Differentiated human neuronal cell lines treated with purified cf-DNA from individuals with MCI and normal cognition will be evaluated for changes in inflammatory cytokine production, activation of NF-kB signaling, and cell death (Aim 2). This innovative study has the potential to identify important immune signaling pathways to examine further in the context of AD and can directly impact patient care by utilizing cf-DNA as a marker associated with rates of disease progression in individuals with MCI.