Neurobiology of Mild Cognitive Impairment in the Elderly

总体数据摘要/摘要 阿尔茨海默病（AD）是一种破坏性的进行性神经退行性疾病，影响超过600万老年人， 在美国，没有可行的治疗方案。因此，定义最早的蜂窝和 推动痴呆症临床前阶段发展新疾病的分子机制 治疗是全世界公共卫生的优先事项。我们的PPG的主旨是“轻度神经生物学”， 老年人认知功能障碍”仍然是阐明细胞和分子基础或链， 从无认知损害（NCI）至轻度认知损害（MCI）的事件，时间点 被认为是治疗痴呆症最有可能的治疗窗口。此外，我们继续专注于我们的 在具有提示临床前AD的AD病理学的NCI受试者中的努力，以解决分子和 细胞性神经致病性后遗症是疾病的临床前阶段的基础。我们将实施一系列 以胆碱能基底前脑（CBF）-默认模式网络为中心的相关连接体项目 (DMN)电路，这是至关重要的记忆和执行功能，并显示早期病理和生物标志物 MCI（前驱AD）之前的活动。CBF神经元功能障碍在临床脑梗死的发病中起着关键作用， 并且是大多数FDA批准的用于AD的药物的基础。此次PPG竞争性续约 应用程序继续汇集了一些基础和临床科学家与多学科， 临床前AD的补充专业知识，以研究基于回路的神经系统功能障碍， 疾病过程的最早阶段。PPG包括管理和临床/组织分布核心， 一个统计和数据管理核心和三个研究项目，题为：Tau Abstract和轻度认知 老年人的损伤Scott Counts，项目负责人，PL，密歇根州立大学，胆碱能基础 老年人前脑神经营养性萎缩和轻度认知障碍（Elliott Mufson，PL，巴罗 神经病学研究所/班纳阿尔茨海默氏症研究所），以及轻度阿尔茨海默病患者的突触和胆碱能抑制 老年人的认知障碍（Milos Ikonomovic，匹兹堡大学）。核心支持每个 项目和所有项目在智力、科学和主题上相互作用。所有核心和项目都利用 相同的拉什宗教秩序研究（RROS）案件和组织的连续性，这赋予了能力， 将生物学测量与认知和神经病理学标准相关联。缺乏真正的动物模型， 当前药物缺乏疗效使得我们的人类临床病理学研究特别相关， 了解临床前AD的机制。

OVERALL PROGRAM SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disorder affecting >6 million older people in the USA for which there is no viable treatment option. Accordingly, defining the earliest cellular and molecular mechanisms that drive the preclinical phase of dementia to develop novel disease modifying therapeutics is a public health priority worldwide. The thrust of our PPG entitled “Neurobiology of Mild Cognitive Impairment in the Elderly” continues to be to elucidate the cellular and molecular basis or chain of events leading from no cognitive impairment (NCI) to mild cognitive impairment (MCI), the time-points considered the most likely therapeutic windows for treating dementia. Moreover, we continue to focus our efforts on NCI subjects with AD pathology suggestive of preclinical AD, in order to resolve the molecular and cellular neuropathogenic sequela underlying this preclincal stage of the disease. We will implement a series of interrelated connectome projects centered on the cholinergic basal forebrain (CBF)-default mode network (DMN) circuit, which is critical for memory and executive function and displays early pathology and biomaker activity prior to MCI (prodromal AD). CBF neuron dysfunction plays a pivotal role in the onset of clinical dementia and is the basis for the majority of FDA approved drugs for AD. This PPG competitive renewal application continues to bring together a number of basic and clinical scientists with multidisciplinary, complementary expertise in preclinical AD to investigate circuit-based neuronal system dysfunction at the earliest stages in the disease process. The PPG includes an Administrative & Clinical/Tissue Distribution Core, a Statistics & Data Management Core and three research projects titled: Tau Abnormalities and Mild Cognitive Impairment in the Elderly Scott Counts, Project Leader, PL, Michigan State University, Cholinergic Basal Forebrain Neurotrophic Abnormalities and Mild Cognitive Impairment in the Elderly (Elliott Mufson, PL, Barrow Neurologic Institute/Banner Alzheimer’s Institute), and Synaptic and Cholinergic Abnormalities in Mild Cognitive Impairment in the Elderly (Milos Ikonomovic, PL University of Pittsburgh). The Cores support each Project and all Projects interact intellectually, scientifically, and thematically. All Cores and Projects utilize the same Rush Religious Orders Study (RROS) cases and tissues for continuity, which confers the ability to correlate biologic measures with cognitive and neuropathological criterion. The lack of true animal models and a lack of efficacy of current drugs make our human clinical pathological studies particularly relevant for understanding mechanisms of preclinical AD.