Microstructural changes in gray and white matter in aging and AD

项目总结 越来越多的神经病理和动物研究表明阿尔茨海默病的病理影响脑微结构 在该病临床表现出现前数年。涉及到各种过程，包括树突的变化 树枝和棘突，轴突形态，突触密度，轴突运输和堆积。直到最近， 对这些微结构特征的评估及其与AD病理的关系一直是主要的 仅限于死后组织。核磁共振技术的最新进展为我们提供了测量 皮质和白质的微结构特征，如轴突形态和大分子组织 人体内的含量。在拟议的研究中，我们将使用一组先进的定量MRI序列 和分析方法，以测量皮质和白质神经突起形态和 临床前阿尔茨海默病的大分子含量，并将检查它们与认知结果的关系，以及 PET测量淀粉样蛋白和tau病理改变。我们最近在以下方面展示了这些措施的有效性 检测健康人大脑皮质和脑白质突起和大分子含量的变化 老年人和遗忘性轻度认知障碍患者。我们还测试了该协会 在一小部分确诊为AD病理的老年人中，这些措施与AD病理之间的关系。 与早期AD表征和AD病理专家合作，并利用斯坦福ADRC PET- MR和深层表型资源，我们将在120名老年人样本中研究以下目标 有认知正常对照(HC)或轻度认知障碍的临床共识诊断 (Mci)，并将根据ADRC淀粉样PET数据确认为Aβ-或Aβ+。我们将检查交叉- 皮质微结构特性的断面和纵向变化，包括轴突密度(NDI)和 取向弥散指数(ODI)(目标1)，以及白质微结构和大分子组织 属性，包括NDI、ODI和大分子组织体积(MTV)(目标2)以及它们之间的关系 通过正电子发射计算机断层扫描确定认知结果和AD病理。采用网络神经科学的方法，我们将 还将检查临床前AD的结缔组织水平微结构变化，并将测试多层 将跨模式(微观结构、分子、正电子发射计算机断层扫描、认知)的测量集成到 捕捉AD的异质性。建议对微观结构和分子进行系统研究 临床前阿尔茨海默病的皮质和白质改变及其与AD病理和认知功能的关系 一个特征良好的临床前AD样本的结果可以为AD的发展提供独特的见解 在疾病的早期阶段，可以显著提高我们对阿尔茨海默病的机制认识。这个 结果也有可能为实验性治疗的发展提供信息，监测他们的 有效性，并预测临床前AD患者的认知和临床轨迹。

PROJECT SUMMARY Accumulating neuropathological and animal studies suggest that AD pathology impacts brain microstructure years before clinical manifestation of the disease. Various processes involved including alterations in dendritic arborization and spines, neurite morphology, synaptic density, and axonal transport and packing. Until recently, the evaluation of these microstructural properties and their association with AD pathology has been mainly limited to postmortem tissue. Recent advances in MRI techniques have provided us with the ability to measure cortical and white matter microstructural properties such as neurite morphology and macromolecular tissue content in human in vivo. In the proposed study, we will employ a set of advanced quantitative MRI sequences and analytical approaches to measure changes in cortical and white matter neurite morphology and macromolecular content in preclinical AD and will examine their association with cognitive outcomes, and amyloid and tau pathology measured by PET. We have recently demonstrated the utility of these measures in detecting alterations in cortical and white matter neurite and macromolecular content in a sample of healthy older adults and patients with amnestic mild cognitive impairment. We have also tested the association between these measures and AD pathology in a small sample of older adults with confirmed AD pathology. Teaming up with experts in early AD characterization and AD pathology and leveraging Stanford ADRC PET- MR and deep phenotyping resources, we will study the following aims on a sample of 120 older adults who have a clinical consensus diagnosis of either cognitively normal controls (HC) or mild cognitive impairment (MCI), and will be confirmed to be Aβ- or Aβ+ based on ADRC amyloid PET data. We will examine cross- sectional and longitudinal changes in cortical microstructural properties including neurite density (NDI) and orientation dispersion index (ODI) (Aim 1), and in white matter microstructural and macromolecular tissue properties including NDI, ODI and macromolecular tissue volume (MTV) (Aim 2), along with their association with cognitive outcomes and AD pathology identified by PET. Taking a network-neuroscience approach, we will also examine connectome-level microstructural changes in preclinical AD and will test the utility of a multi-layer network framework for integrating measures across modalities (microstructural, molecular, PET, cognition) to capture the heterogeneity of AD. The proposed systematic investigation of microstructural and molecular changes in cortical and white matter in preclinical AD and their association with AD pathology and cognitive outcomes in a well-characterized preclinical AD sample can provide unique insight regarding AD development in early stages of the disease and can significantly improve our mechanistic understanding of AD. The outcomes also have the potential to inform development of experimental treatments, monitoring their effectiveness, and predicting cognitive and clinical trajectories of preclinical AD patients.