Quantitative Neuroimaging Assessment of White Matter Integrity in the Context of Aging and AD

衰老和 AD 背景下白质完整性的定量神经影像评估

• 批准号: 10589468
• 负责人: Andreana Benitez
• 金额: $ 127.4万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589468
• 关键词: 3-Dimensional; Address; Age; Aging; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Axon; Biological Assay; Biological Markers; Brain; Clinical; Clinical Research; Clinical Trials; Cognitive; Data; Dementia; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Elderly; Failure; Fiber; Funding; Geometry; Gliosis; Goals; Grant; Health; Hippocampus; Image; Impaired cognition; Inflammation; Knowledge; Lesion; Longitudinal Studies; Longitudinal cohort; Longitudinal cohort study; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Measures; Methods; Microscopic; Modeling; Monitor; Myelin; Myelin Water Imaging; N-acetylaspartate; Natural History; Natural Immunity; Nerve Degeneration; Neuroglia; Neuropsychological Tests; Outcome Study; Participant; Pathologic; Phase; Positron-Emission Tomography; Procedures; Process; Questionnaires; Relaxation; Risk Factors; Sample Size; Signal Transduction; Structure; Techniques; Testing; Time; Tissues; Visualization; Water; Work; age related; aging brain; amyloid imaging; amyloid pathology; asymptomatic Alzheimer' s disease; beta amyloid pathology; biophysical model; clinically relevant; cohort; data modeling; density; follow-up; innovation; magnetic resonance imaging biomarker; mild cognitive impairment; myoinositol; neuroimaging; neuroimaging marker; normal aging; pandemic disease; pathological aging; pre-clinical; pre-clinical therapy; prevent; recruit; repaired; response; retention rate; senescence; therapy development; trend; white matter; white matter change

PROJECT SUMMARY Although the most significant risk factor for developing Alzheimer’s disease (AD) is advanced age, the changes in tissue microstructure that signal the shift from normal aging to AD are not well understood. Thus, in response to PAR-22-093, NOT-AG-21-039: Understanding AD in the Context of the Aging Brain, we seek to elucidate the changes in white matter microstructure in preclinical AD using advanced diffusion MRI methods developed by our group. During the 1st funding period of this grant, we established a longitudinal cohort of 165 cognitively unimpaired participants ages 45-85 who completed extensive clinical procedures (i.e. MRI, amyloid PET, neuropsychological testing, questionnaires), with an exceptional 92% retention rate at 2-year follow-up, including 14% of participants who have developed incident mild cognitive impairment (MCI) thus far. We showed that in participants with preclinical AD, late-myelinating white matter tracts demonstrate signs of myelin repair/gliosis as evidenced by greater diffusion restriction. We also observed that greater diffusion restriction in the hippocampus significantly predicts incident MCI over and above age, a finding we did not observe with other AD neuroimaging biomarkers of amyloid pathology, neurodegeneration, and white matter lesions. These results have significant implications for disease monitoring and treatment development for the very earliest stages of AD, but further work is needed to refine these methods and determine how they indicate both aging and disease progression over time. Thus, during the 2nd funding period, we seek to continue studying this cohort longitudinally every 2 years, to enhance the cohort’s inclusivity and sample size, and to add new, complementary MRI biomarkers of myelin/gliosis to test our inferences. Our overall objective is to delineate the natural history of white matter changes from normal aging to preclinical AD and to MCI/dementia, illuminating what aspects of myelin/gliosis drive changes in diffusivity, where these preferentially occur, and when in the course of disease these take place. We will continue leveraging our interdisciplinary group’s expertise in diffusion MRI (Diffusional Kurtosis Imaging, Fiber Ball Imaging) and biophysical modeling, adding new experts on T1-based myelin water imaging and 1H- Magnetic Resonance Spectroscopy to assay myelin dynamics/gliosis. We hypothesize that advanced diffusion MRI methods can indicate myelin repair/gliosis in the preclinical stage prior to myelin breakdown and axonal loss in the symptomatic stage, a trajectory that is distinct from normal, homeostatic processes such as myelin remodeling/maintenance. Thus, we aim to: Characterize longitudinal changes in white matter microstructure in aging and AD (Aim 1); Quantify microscopic axonal fiber organization in aging and AD (Aim 2); Determine the associations between diffusion MRI-derived microstructural parameters and complementary measures of myelin/gliosis in aging and AD (Aim 3). This work will have the greatest overall impact in providing the critical translational support for trials that target mechanisms such as innate immunity/inflammation and glial senescence, which are very promising yet grossly underexplored in AD especially for the asymptomatic stage.

项目摘要 尽管发展阿尔茨海默氏病（AD）最重要的危险因素是高龄，但变化 在信号的组织微观结构中，从正常衰老到AD的转移尚不清楚。那是为了回应 至22-093，NOT-AG-21-039：在衰老大脑的背景下了解AD，我们试图阐明 使用高级扩散MRI方法开发的临床前AD中白质微观结构的变化 我们的小组。在这笔赠款的第一个资金期间，我们建立了165个纵向队列 完成广泛临床程序的45-85岁的独立参与者（即MRI，淀粉样蛋白宠物， 神经心理学测试，问卷），在2年随访中的保留率为92％，包括 到目前为止，患有事件的轻度认知障碍（MCI）的参与者中有14％。我们在 临床前广告的参与者，晚熟白质区域显示髓磷脂修复/神经胶质的迹象为 通过更大的扩散限制证明。我们还观察到海马的扩散限制更大 显着预测了超过年龄的事件MCI，这一发现我们没有观察到其他AD神经影像学 淀粉样病理学，神经变性和白质病变的生物标志物。这些结果具有显着 AD的早期阶段对疾病监测和治疗发展的影响，但进一步 需要工作来完善这些方法并确定它们如何指示衰老和疾病进展 随着时间的推移。在第二个资金期间，我们试图继续每2次纵向研究此队列 多年，以增强队列的包容性和样本量，并添加新的，完整的MRI生物标志物 髓磷脂/神经胶质病以测试我们的信息。我们的总体目标是描述白质的自然历史 从正常衰老到临床前广告再到MCI/痴呆症的变化，阐明了髓磷脂/神经胶质的哪些方面 驱动难度变化，更优选地发生的情况以及在疾病过程中发生的驱动变化。 我们将继续利用跨学科小组在扩散MRI方面的专业知识（扩散峰度成像， 纤维球成像）和生物物理建模，添加了基于T1的髓鞘水成像和1H-的新专家 磁共振光谱法测定髓磷脂动力学/神经胶质。我们假设高级扩散 MRI方法可以指示髓磷脂分解和轴突损失之前的临床前阶段的髓磷脂修复/神经胶质 在有症状的阶段，与正常的稳态过程（如髓鞘）不同的轨迹 改建/维护。这就是我们的目的：在白质微观结构中的纵向变化表征 衰老和广告（目标1）；量化衰老和AD中的微观轴突纤维组织（AIM 2）；确定 扩散MRI衍生的微结构参数与完整测量之间的关联 衰老和AD中的髓磷脂/神经病（AIM 3）。这项工作将对提供关键的总体影响最大 针对诸如先天免疫/炎症和神经胶质等机制的试验的转化支持 敏感，非常有望在AD中严重忽略，尤其是在无症状阶段。