Memory Circuitry in MCI and Early Alzheimerâs Disease Prodrome: Molecular Drivers

摘要 该研究计划的更新解决了阿尔茨海默病（AD）研究中的两个关键瓶颈： 早期检测风险患者，并在临床前和早期阶段识别重要的生物学过程 疾病的阶段。这些挑战是诊断和治疗方法发展的关键， 以及需要在痴呆症发作前至少5-10年实施的预防战略。 在上一个资助期间，该项目提供了关于轻度遗忘症患者的新信息。 认知障碍（MCI），并帮助推动该领域对MCI前阶段的重点。一项重大创新 研究对象是有正常认知障碍的心境正常的老年人， 认知测试的范围在这一组中，我们报告了大脑结构的改变，功能激活， 以及与记忆相关的区域的网络中的连通性， 在认知正常对照（CN）和MCI患者中可见。这种表型，现在被称为 2013年，一个国际共识小组定义了主观认知下降（SCD）， 包括阿尔茨海默病神经影像学倡议（ADNI）在内的大规模研究， 认知变化指数（CCI）在这个项目中开发招募一个类似的组（SMC）。我们驾驶了一架双- 示踪PET方法来研究作为疾病阶段的函数的分子特征， 淀粉样蛋白负荷与免疫激活（小胶质细胞）的关系。随着PET示踪剂的新推出， 由于tau负荷的体内测量，我们将测量临床前和前驱阶段的tau和淀粉样蛋白， AD，侧重于基于神经病理学研究的靶向区域。淀粉样蛋白和tau蛋白沉积的作用 作为大脑活动和连接的早期功能中断的分子驱动器，以及 神经退行性变，将使用先进的MRI方法的集成集成进行研究，包括 结构MRI、记忆任务和静息状态fMRI、动脉自旋标记灌注（3D pCASL）和弥散 在Prisma 3 T平台上使用64通道RF线圈和新的多波段采集进行成像（DTI和NODDI） 序列的储存和分析液体生物标志物（血液、CSF）以及分析APOE和其他候选 基因将提供一个生物学背景和新的机会，以了解非常早期的变化，从一个系统， 生物学角度。本研究的总体目标是验证早期预后生物标志物， 通过完成三个具体的实验， 目的：（1）确定大脑活动和连接功能中断的阶段特异性特征，tau蛋白和 淀粉样蛋白负荷、微血管病理学、神经退行性变和临床前和前驱期炎症 AD;（2）确定病理生理学领域之间的时间关系和相互作用;以及（3） 确定哪种基线标志物组合最能预测随访时的临床和MRI进展- 起来这项研究的最终影响是促进有效的AD精准医学的发展。

Abstract The renewal of this research program addresses two critical bottlenecks in Alzheimer's disease (AD) research: earlier detection of those at risk and identification of important biological processes during preclinical and early stages of disease. These challenges are the key to development of diagnostic and therapeutic approaches, as well as prevention strategies that will need to be implemented at least 5-10 years before dementia onset. During the prior funding period, this project contributed novel information on individuals with amnestic mild cognitive impairment (MCI) and helped drive the field toward a focus on pre-MCI stages. A major innovation has been the investigation of euthymic older adults with cognitive complaints that score within the normal range on cognitive testing. In this group we have reported alterations in brain structure, functional activation, and connectivity in a network of memory-related regions that are typically intermediate between the pattern seen in cognitively normal controls (CN) and individuals with MCI. This phenotype, now referred to as subjective cognitive decline (SCD) and defined by an international consensus panel in 2013, is influencing large-scale studies including the Alzheimer's Disease Neuroimaging Initiative (ADNI), which adopted the Cognitive Change Index (CCI) developed in this project to recruit a similar group (SMC). We piloted a dual- tracer PET approach to study molecular signatures as a function of stage of disease, initially examining the relationship of amyloid burden and immune activation (microglia). With the new availability of PET tracers for in vivo measurement of tau burden, we will measure both tau and amyloid in preclinical and prodromal stages of AD, focusing on targeted regions based on neuropathological studies. The role of amyloid and tau deposition as molecular drivers of early functional disruption of brain activity and connectivity, as well as neurodegeneration, will be investigated using an integrated ensemble of advanced MRI approaches including structural MRI, memory task and resting state fMRI, arterial spin labeled perfusion (3D pCASL), and diffusion imaging (DTI and NODDI) on the Prisma 3T platform with 64 channel RF coil and new multiband acquisition sequences. Banking and analysis of fluid biomarkers (blood, CSF) and analysis of APOE and other candidate genes will provide a biological context and new opportunities to understand very early changes from a systems biology perspective. The overall objectives of this research are to validate early prognostic biomarkers and enhance the understanding of biological mechanisms in early stages through accomplishing three specific aims: (1) Determine the stage-specific profile of functional disruption of brain activity and connectivity, tau and amyloid burden, microvascular pathology, neurodegeneration, and inflammation in preclinical and prodromal AD; (2) Determine the temporal relationships and interactions among pathophysiological domains; and (3) Determine which combination of baseline markers is most predictive of clinical and MRI progression on follow- up. The ultimate impact of this research is to facilitate the development of effective precision medicine for AD.