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

项目概要/摘要 背景：随着认知能力下降是我们老龄化人口日益严重的健康问题， 越来越重要的是，更好地表征导致年龄相关认知功能障碍的神经生物学变化， 损伤和痴呆。尽管神经影像学方法在检测微结构方面显示出了希望， 与认知能力下降和阿尔茨海默病（AD）相关的大脑变化，需要生物标志物 提高了对疾病最早期的敏感性，此时治疗可能最有效。新兴 研究表明，当认知障碍仍然轻微时， 并且可能在脑萎缩之前。需要进一步的研究来了解BBB通透性的变化 在AD的过程中，以及它如何与大脑微观结构，形态测量学和 分子病理学 初步研究：我们的初步研究表明，限制性光谱成像（RSI）的敏感性， 在轻度认知障碍（MCI）和早期AD中的微结构脑变化。RSI、认知功能和 测量了31名健康对照（HC）、12名MCI患者和13名轻度AD患者的CSF淀粉样蛋白-β。 神经突密度（ND），一种限制水扩散的措施，占交叉纤维，较低， MCI/AD的几个白色物质束和灰质各向同性自由水扩散（IF）高于HC。 ND和IF与情景记忆和淀粉样蛋白-β负荷相关。 拟定研究：动态对比增强MRI、RSI、结构MRI、CSF淀粉样蛋白-β和tau，以及 将获得15例AD遗传风险低的HC（APOE 4非携带者）和15例 MCI患者。将比较各组之间的BBB渗透性，并与记忆相关 性能、RSI测量、形态测定和淀粉样蛋白/tau蛋白，以测试BBB破坏是否与 前驱期微结构变化、认知障碍和已建立的AD生物标志物 AD（目标1）。在R 00阶段，将收集40例HC的神经影像学、CSF和认知数据， AD遗传风险，70例AD遗传风险升高的HC（APOE 4携带者）和70例MCI患者。所有 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崩溃和RSI指标可预测认知功能下降，对临床前AD敏感（Aim 2A）。 来自所有阶段的数据将被组合以模拟BBB渗透性、脑渗透性和脑组织渗透性的变化模式。 从正常到前驱AD的显微结构和分子病理学（Aim 2B）。淀粉样蛋白PET将是 对参与者的子集（31个淀粉样蛋白阴性HC，37个淀粉样蛋白阳性HC，31个MCI）进行测试， 假设血脑屏障破裂与淀粉样蛋白沉积相关并共定位， APOE 4携带者中BBB渗透性增加与淀粉样蛋白之间的联系比非携带者更大 载体（目标3）。

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).