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.

项目摘要 累积神经病理学和动物研究表明，AD病理学会影响脑微观结构 疾病临床表现前几年。涉及的各种过程，包括树突状的改变 树博化和刺，神经形态，突触密度以及轴突的运输和包装。直到最近， 这些微结构特性的评估及其与AD病理学的关联主要是 仅限于死后组织。 MRI技术的最新进展为我们提供了测量的能力 皮质和白质微观结构特性，例如神经形态和大分子组织 在人体体内内容。在拟议的研究中，我们将采用一组高级定量MRI序列 以及衡量皮质和白质神经病形态变化的分析方法以及 临床前广告中的大分子含量，将检查它们与认知结果的关联，并将 通过PET测量的淀粉样蛋白和TAU病理学。我们最近证明了这些测量的实用性 在健康样本中检测皮质和白质神经蛋白和大分子含量的改变 老年人和患有轻度轻度认知障碍的患者。我们还测试了协会 这些措施和AD病理学的一小部分老年人患有确认的AD病理学。 与早期广告表征和广告病理学专家合作，并利用Stanford Adrc Pet- MR和深层表型资源，我们将研究以下目标，以120名老年人的样本 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数据确认为Aβ-或Aβ+。我们将检查交叉 皮质微结构特性的分段和纵向变化，包括神经元密度（NDI）和 方向分散指数（ODI）（AIM 1），以及白质微结构和大分子组织 包括NDI，ODI和大分子组织体积（MTV）在内的特性（AIM 2），以及它们的关联 具有PET确定的认知结果和AD病理学。采用网络神经科学方法，我们将 还要检查临床前AD中的连接级级微结构变化，并将测试多层的实用性 网络框架用于整合跨模态的度量（微结构，分子，宠物，认知） 捕获AD的异质性。提出的微观结构和分子的系统研究 临床前广告中皮质和白质的变化及其与AD病理学和认知的关联 特征良好的临床前广告样本中的结果可以提供有关广告开发的独特见解 在疾病的早期阶段，可以显着提高我们对AD的机械理解。 结果还有可能告知实验治疗的开发，监视其 有效性，并预测临床前AD患者的认知和临床轨迹。