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 虽然发展阿尔茨海默病（AD）的最重要的风险因素是高龄，但这种变化 在组织微结构中，从正常老化到AD转变信号还没有很好地理解。因此，作为回应， 根据PAR-22-093、NOT-AG-21-039：在大脑老化的背景下了解AD，我们试图阐明 使用由开发的先进扩散MRI方法，临床前AD的白色微结构变化 我们的团队在该资助的第一个资助期内，我们建立了一个由165名认知障碍者组成的纵向队列， 年龄在45-85岁的未受损参与者完成了广泛的临床程序（即MRI，淀粉样蛋白PET， 神经心理学测试，问卷调查），2年随访时留存率为92%，包括 到目前为止，14%的参与者发生了轻度认知障碍（MCI）。我们展示了 患有临床前AD、髓鞘形成晚期白色物质束的参与者表现出髓鞘修复/神经胶质增生的迹象， 这是由更大的扩散限制证明的。我们还观察到海马区的扩散限制更大， 显著预测年龄以上的MCI事件，这一发现我们在其他AD神经影像学中没有观察到 淀粉样蛋白病理学、神经变性和白色物质病变的生物标志物。这些结果具有显著的 对AD最早期的疾病监测和治疗开发的影响，但进一步 需要进一步完善这些方法，并确定它们如何指示衰老和疾病进展 随着时间因此，在第二个资助期内，我们寻求继续纵向研究这一队列，每2 年，以提高队列的包容性和样本量，并增加新的，互补的MRI生物标志物， 髓鞘/神经胶质增生来检验我们的推断我们的总体目标是描绘出白色物质的自然历史 从正常衰老到临床前AD和MCI/痴呆的变化，阐明了髓鞘/神经胶质增生的哪些方面 驱动扩散率的变化，这些变化优先发生在哪里，以及在疾病过程中这些变化何时发生。 我们将继续利用我们跨学科小组在弥散MRI（弥散峰度成像， 纤维球成像）和生物物理建模，增加了T1为基础的髓鞘水成像和1H- 磁共振波谱分析髓鞘动力学/神经胶质增生。我们假设高级扩散 MRI方法可以指示在髓鞘破坏和轴突损失之前的临床前阶段的髓鞘修复/神经胶质增生 在症状阶段，一个不同于正常的稳态过程的轨迹，如髓鞘 改造/维护。因此，我们的目标是：表征白色物质微观结构的纵向变化， 衰老和AD（目标1）;量化衰老和AD中的微观轴突纤维组织（目标2）;确定 扩散MRI衍生的微观结构参数和互补措施之间的关联 髓鞘/神经胶质增生在衰老和AD中的作用（目的3）。这项工作将产生最大的总体影响， 为针对先天免疫/炎症和神经胶质细胞等机制的试验提供翻译支持 衰老，这是非常有前途的，但严重不足的探索，特别是在AD的无症状阶段。