Association of blood-brain barrier breakdown with brain microstructure neuropathology in early Alzheimer's Disease

早期阿尔茨海默病中血脑屏障破坏与脑微结构神经病理学的关系

• 批准号: 10633267
• 负责人: Emilie T. Reas
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10633267
• 关键词: Age-associated memory impairment; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid deposition; Area; Atrophic; Biological; Biological Markers; Blood - brain barrier anatomy; Brain; Cell Death; Clinical; Cognitive; Complex; Data; Dementia; Deposition; Detection; Diffusion; Dimensions; Disease; Disease Progression; Edema; Elderly; Ensure; Episodic memory; Evolution; Excision; Fiber; Functional disorder; Genetic Risk; Guidelines; Health; Hemorrhage; Image; Imaging Techniques; Impaired cognition; Individual; Intervention; Knowledge; Lead; Magnetic Resonance Imaging; Measurable; Measures; Medial; Memory; Memory Disorders; Memory impairment; Methodology; Methods; Microscopic; Modeling; Modification; Molecular; Nerve Degeneration; Neurites; Neurobehavioral Manifestations; Neurobiology; Neurofibrillary Tangles; Neuropsychology; Participant; Pathogenesis; Pathologic; Patients; Pattern; Performance; Physiological; Pilot Projects; Population; Positron-Emission Tomography; Process; Quality of life; Research; Restriction Spectrum Imaging; Safety; Severity of illness; Structure; Symptoms; Synapses; Temporal Lobe; Testing; Time; Visualization; aging population; apolipoprotein E-4; blood-brain barrier disruption; blood-brain barrier permeabilization; cerebral atrophy; cerebrovascular; cognitive function; contrast enhanced; density; follow-up; gray matter; human old age (65+); improved; in vivo; mild cognitive impairment; molecular marker; molecular pathology; morphometry; neural; neuroimaging; neuropathology; neurovascular; normal aging; pre-clinical; prodromal Alzheimer' s disease; research clinical testing; stem; tau Proteins; treatment optimization; water diffusion; white matter; β-amyloid burden

PROJECT SUMMARY/ABSTRACT Background: As cognitive decline is a mounting health concern for our aging population, it is becoming increasingly important to better characterize the neurobiological changes leading to age-related cognitive impairment and dementia. Although neuroimaging methods have shown promise at detecting microstructural brain changes associated with cognitive decline and Alzheimer's disease (AD), there is need for biomarkers with improved sensitivity to the earliest disease stages, when treatments may be most effective. Emerging research suggests that blood-brain barrier (BBB) breakdown occurs when cognitive impairments are still mild, and may precede brain atrophy. Further research is needed to understand how BBB permeability changes over the course of AD and how it relates to established markers of brain microstructure, morphometry and molecular pathology. Preliminary Studies: Our pilot study demonstrated sensitivity of Restriction Spectrum Imaging (RSI) to microstructural brain changes in Mild Cognitive Impairment (MCI) and early AD. RSI, cognitive function and CSF amyloid-β were measured in 31 healthy controls (HC), 12 individuals with MCI and 13 with mild AD. Neurite density (ND), a measure of restricted water diffusion that accounts for crossing fibers, was lower in several white matter tracts, and gray matter isotropic free water diffusion (IF) was higher for MCI/AD than HC. ND and IF correlated with episodic memory and with amyloid-β burden. Proposed Studies: Dynamic contrast-enhanced MRI, RSI, structural MRI, CSF amyloid-β and tau, and neuropsychological data will be acquired on 15 HC with low genetic risk for AD (APOE4 non-carriers) and 15 individuals with MCI. BBB permeability will be compared between groups and correlated with memory performance, RSI measures, morphometry and amyloid/tau to test whether BBB breakdown is associated with microstructural changes, cognitive impairment and established AD biomarkers during prodromal AD (Aim 1). During the R00 stage, neuroimaging, CSF and cognitive data will be collected on 40 HC with low genetic risk for AD, 70 HC with elevated genetic risk for AD (APOE4 carriers) and 70 individuals with MCI. All participants will be clinically and cognitively evaluated 2-3 years after baseline to test the hypothesis that BBB breakdown and RSI metrics predict cognitive decline and are sensitive to preclinical AD (Aim 2A). Data from all stages will be combined to model patterns of change in BBB permeability, brain microstructure and molecular pathology from normal to prodromal AD (Aim 2B). Amyloid PET will be performed on a subset of participants (31 amyloid-negative HC, 37 amyloid-positive HC, 31 MCI) to test the hypotheses that BBB breakdown correlates and colocalizes with amyloid deposition, and that the association between increased BBB permeability and amyloid is greater in APOE4 carriers than non- carriers (Aim 3).

项目摘要/摘要 背景：由于认知能力下降是我们老龄化人口的越来越多的健康问题，因此它正在变得 越来越重要，以更好地表征导致与年龄相关的认知的神经生物学变化 障碍和痴呆症。尽管神经影像学方法已经显示出检测微结构的希望 与认知能力下降和阿尔茨海默氏病（AD）相关的大脑变化，需要生物标志物 当治疗最有效时，对最早的疾病阶段的敏感性提高了。新兴 研究表明，当认知障碍仍然轻度时，会发生血脑屏障（BBB）崩溃 并可能先于大脑萎缩。需要进一步的研究来了解BBB渗透率如何变化 在AD的过程中及其与脑微结构，形态计量学和 分子病理学。 初步研究：我们的试点研究表明限制频谱成像（RSI）对 轻度认知障碍（MCI）和早期AD的微观结构大脑变化。 RSI，认知功能和 在31个健康对照（HC），12个患有MCI的人和13个轻度AD的人中测量了CSF淀粉样蛋白-β。 神经突密度（ND）是跨越纤维的限制性水扩散度量的量度，较低 MCI/AD的几个白质区和灰质各向同性的游离水扩散（如果）高于HC。 nd，如果与情节记忆和淀粉样蛋白β负担相关。 拟议的研究：动态对比增强的MRI，RSI，结构MRI，CSF淀粉样蛋白β和TAU，以及 神经心理学数据将在15 HC上获取，其AD（APOE4非载体）和15 患有MCI的人。 BBB渗透性将在组之间进行比较，并与内存相关 性能，RSI测量，形态计和淀粉样蛋白/TAU测试BBB分解是否相关 在前沿期间，随着微观结构的变化，认知障碍和建立的AD生物标志物 广告（目标1）。在R00阶段，将在40 HC上收集神经影像学，CSF和认知数据 AD的遗传风险，AD（APOE4载体）遗传风险升高的70 HC和70名MCI患者。全部 参与者将在基线后2 - 3年进行临床和认知评估，以检验以下假设。 BBB分解和RSI指标可以预测认知能力下降，并且对临床前AD敏感（AIM 2A）。 来自所有阶段的数据将结合到BBB渗透率的变化模型模式 从正常到前驱AD（AIM 2B）的微观结构和分子病理学。淀粉样宠物将 在参与者的一部分（31个淀粉样蛋白阴性HC，37个淀粉样蛋白阳性HC，31 MCI）上进行测试 BBB崩溃与淀粉样蛋白沉积相关并共定位的假设，并且 在APOE4载体中，BBB渗透率增加和淀粉样蛋白之间的关联比非非 - 载体（AIM 3）。