Hippocampal and parietal network changes among subjects in the early phases of AD and relationship with CSF biomarkers

项目1项目摘要/摘要 阿尔茨海默病-S病(AD)的病理可以在大脑中观察到许多年甚至几十年前 由此导致的痴呆症的发病提供了一个机会之窗，在那里干预可能会有最大的效果 成功的机会。在这一前驱期观察到的改变涉及多个可区分的神经 大脑中的网络，包括内侧颞叶和顶叶网络。特别是，增加了 功能磁共振成像(FMRI)观察轻度痴呆患者的海马区激活 认知障碍(MCI)似乎会导致记忆功能障碍，因此可能会被用于 作为AD病理学早期发展的标志物。然而，目前还不清楚这种海马亚 区域特异性功能障碍与其他fMRI改变有关，通常在早期观察到 本病如顶叶网络改变或内侧颞叶之间的功能连接改变 和顶叶网络。此外，目前还不清楚这些fmri变化与已建立的 AD病理的生物标志物，如脑脊液A-�、tau和p-tau的测量。最后，它 目前尚不清楚是否可以在认知方面观察到海马、顶叶或功能连接性的变化 有严重记忆问题的正常人，可能代表着更早的阶段 广告连续体。目前的项目建议以高分辨率直接解决这些问题 海马区和顶区神经网络功能的神经影像研究 这些网络及其与脑脊液中A-�、tau和p-tau测定的关系 公元的连续体。将采用有针对性的功能磁共振激活任务，旨在对海马子区域征税 特殊功能和顶网功能。将使用高分辨率的静息状态功能磁共振成像来评估 海马区和顶区网络之间的连通性改变。将收集脑脊液样本以评估 这些神经网络改变与脑脊液A�、tau和p-tau测定的关系。这些方法将是 受试者分为四组：(1)有主观记忆顾虑的认知正常受试者； (2)早期MCI组(EMCI)，(3)晚期MCI组(LMCI)，(4)健康对照组。团结在一起 拟议中的研究将深入了解与海马体和脑组织相关的脑功能变化 LMCI和EMCI受试者的顶叶网络功能障碍和这些网络之间的功能连接， 与对照组比较，并确定SMC受试者是否表现出类似的异常。这些研究将 从而阐明了这些神经网络的变化、认知表现和 在早期疾病谱的受试者中，阿尔茨海默病病理在大脑中的累积。最后，这项工作 可以提供证据，表明功能磁共振测量的海马区网络功能障碍是否可以作为一种标志物 为AD病理学的早期发展奠定了基础。

PROJECT 1 PROJECT SUMMARY / ABSTRACT Alzheimer s disease (AD) pathology can be observed in the brain many years or even decades before the onset of the resulting dementia providing a window of opportunity where intervention may have the greatest chance of success. Observed alterations in this prodromal stage involve multiple distinguishable neural networks in the brain, including the medial temporal and parietal lobe networks. Particularly, increased hippocampal activation observed with functional magnetic resonance imaging (fMRI) in subjects with mild cognitive impairment (MCI) appears to contribute to memory dysfunction and may therefore potentially be used as a marker for the early development of AD pathology. However, it remains unclear if this hippocampal sub region specific dysfunction is associated with other fMRI changes commonly observed in the early stages of the disease, such as parietal network changes or functional connectivity changes between medial temporal and parietal lobe networks. Additionally, it remains unclear how these fMRI changes relate to established biomarkers of AD pathology such as cerebrospinal fluid (CSF) measures of A�, tau and p-tau. Finally, it remains unclear if hippocampal, parietal or functional connectivity changes can be observed in cognitively normal individuals who have a significant memory concern and may represent an even earlier phase along the AD continuum. The current project proposes to directly address these questions in a high-resolution neuroimaging study of hippocampal and parietal network function, examining functional connectivity between these networks and their association with CSF measures of A�, tau and p-tau in subjects along the prodromal continuum of AD. Targeted fMRI activation tasks will be employed designed to tax hippocampal sub region specific function and parietal network function. High-resolution resting state fMRI will be employed to assess connectivity changes between hippocampal and parietal networks. CSF samples will be collected to assess the relationship between these network changes and CSF measures of A�, tau and p-tau. These methods will be employed in four groups of subjects: (1) cognitively normal subjects with subjective memory concerns (SMC), (2) subjects with early MCI (EMCI), (3) late MCI (LMCI), and (4) healthy control subjects. Together the proposed studies will provide insight into the functional brain changes associated with hippocampal and parietal network dysfunction and functional connectivity between these networks in LMCI and EMCI subjects, compared to controls, and determine whether SMC subjects display similar abnormalities. These studies will thus shed light on the relationship between changes in these neural networks, cognitive performance and the accumulation of AD pathology in the brain in subjects across the early spectrum of disease. Finally, this work may provide evidence of whether fMRI measures of hippocampal network dysfunction can serve as a marker for the early development of AD pathology.