Microstructural changes in gray and white matter in aging and AD

衰老和 AD 过程中灰质和白质的微观结构变化

• 批准号: 10446947
• 负责人: Hadi Hosseini
• 金额: $ 78.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446947
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animals; Autopsy; Axonal Transport; Behavior; Brain; Brain Pathology; Clinical; Cognition; Cognitive; Cognitive deficits; Communities; Consensus; Data; Detection; Development; Diagnosis; Diffusion; Disease; Disease Outcome; Effectiveness; Elderly; Evaluation; Heterogeneity; Hippocampus (Brain); Histologic; Human; Image; Impaired cognition; Investigation; Knowledge; Link; Magnetic Resonance Imaging; Maps; Measurement; Measures; Medial; Modality; Modeling; Molecular; Monitor; Morphology; Myelin; Nerve Degeneration; Neurites; Neurobiology; Neurofibrillary Tangles; Neurons; Neurosciences; Outcome; Parietal Lobe; Pathology; Phenotype; Positron-Emission Tomography; Process; Property; Prospective Studies; Reproducibility; Research Personnel; Resources; Sampling; Senile Plaques; Signal Transduction; Synapses; Techniques; Testing; Tissues; Vertebral column; amnestic mild cognitive impairment; base; brain morphology; brain tissue; compare effectiveness; connectome; density; disease heterogeneity; extracellular; gray matter; improved; in vivo; indexing; insight; mild cognitive impairment; neuroimaging; novel; older patient; pre-clinical; predictive marker; prodromal Alzheimer' s disease; tau Proteins; white matter

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.

项目概要 越来越多的神经病理学和动物研究表明 AD 病理学影响大脑微观结构 疾病临床表现前数年，涉及各种过程，包括树突的改变。 树枝化和棘、神经突形态、突触密度以及轴突运输和包装。 对这些微观结构特性及其与 AD 病理学关系的评估主要是 MRI 技术的最新进展为我们提供了测量死后组织的能力。 皮质和白质微观结构特性，例如神经突形态和大分子组织 在拟议的研究中，我们将采用一组先进的定量 MRI 序列。 和测量皮质和白质神经突形态变化的分析方法 临床前 AD 中的大分子内容，并将检查它们与认知结果的关联，以及 我们最近证明了这些措施在 PET 测量中的实用性。 检测健康样本中皮质和白质神经突和大分子含量的变化 我们还测试了老年人和患有遗忘性轻度认知障碍的患者之间的关联。 这些措施与一小部分已确诊 AD 病理的老年人样本中的 AD 病理之间的关系。 与早期 AD 表征和 AD 病理学专家合作，并利用斯坦福 ADRC PET- MR 和深度表型资源，我们将以 120 名老年人为样本研究以下目标 具有认知正常对照 (HC) 或轻度认知障碍的临床共识诊断 (MCI)，并将根据 ADRC 淀粉样蛋白 PET 数据确认是 Aβ- 或 Aβ+。 皮质微结构特性的截面和纵向变化，包括神经突密度（NDI）和 取向色散指数 (ODI)（目标 1），以及白质微观结构和大分子组织 属性，包括 NDI、ODI 和大分子组织体积 (MTV)（目标 2）及其关联 通过 PET 识别认知结果和 AD 病理，我们将采用网络神经科学方法。 还检查临床前 AD 中连接组水平的微观结构变化，并将测试多层的实用性 用于整合跨模式（微观结构、分子、PET、认知）测量的网络框架 捕获 AD 的异质性所提出的微观结构和分子的系统研究。 临床前 AD 中皮质和白质的变化及其与 AD 病理和认知的关系 充分表征的临床前 AD 样本中的结果可以提供有关 AD 发展的独特见解 在疾病的早期阶段，可以显着提高我们对 AD 机制的理解。 结果也有可能为实验治疗的开发提供信息，监测其效果 有效性，并预测临床前 AD 患者的认知和临床轨迹。