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

项目概要/摘要 背景：由于认知能力下降是我们老龄化人口日益关注的健康问题，因此它正在成为 更好地表征导致与年龄相关的认知的神经生物学变化变得越来越重要 损伤和痴呆。尽管神经影像方法在检测微观结构方面显示出希望 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 提高对最早疾病阶段的敏感性，此时治疗可能是最有效的。新兴 研究表明，当认知障碍仍然轻微时，血脑屏障（BBB）就会崩溃， 并且可能先于脑萎缩。需要进一步研究来了解血脑屏障渗透性如何变化 AD 的整个过程以及它如何与已建立的大脑微结构、形态测量和 分子病理学。 初步研究：我们的试点研究证明了限制谱成像 (RSI) 对 轻度认知障碍 (MCI) 和早期 AD 中大脑微观结构的变化。 RSI、认知功能和 在 31 名健康对照者 (HC)、12 名 MCI 患者和 13 名轻度 AD 患者中测量了脑脊液淀粉样蛋白-β。 神经突密度（ND）是衡量纤维交叉的受限水扩散的指标，在 MCI/AD 的多个白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β淀粉样蛋白负担相关。 拟议研究：动态对比增强 MRI、RSI、结构 MRI、CSF 淀粉样蛋白-β 和 tau 蛋白，以及 将获取 15 名 AD 遗传风险较低的 HC（APOE4 非携带者）和 15 名 HC 的神经心理学数据 患有 MCI 的人。将比较各组之间的 BBB 通透性并与记忆相关 性能、RSI 测量、形态测定和淀粉样蛋白/tau 蛋白，以测试 BBB 崩溃是否相关 前驱期发生微观结构变化、认知障碍和已确定的 AD 生物标志物 AD（目标 1）。在 R00 阶段，将在 40 个低水平 HC 上收集神经影像、脑脊液和认知数据。 AD 遗传风险、70 名具有 AD 遗传风险升高的 HC（APOE4 携带者）和 70 名 MCI 个体。全部 参与者将在基线后 2-3 年接受临床和认知评估，以检验以下假设： BBB 崩溃和 RSI 指标可预测认知能力下降，并且对临床前 AD 敏感（目标 2A）。 来自所有阶段的数据将被结合起来，以模拟 BBB 通透性、大脑的变化模式。 从正常到前驱 AD 的微观结构和分子病理学（目标 2B）。淀粉样蛋白 PET 将 对一部分参与者（31 名淀粉样蛋白阴性 HC、37 名淀粉样蛋白阳性 HC、31 名 MCI）进行测试，以测试 假设 BBB 分解与淀粉样蛋白沉积相关并共定位，并且 APOE4 携带者中 BBB 通透性增加与淀粉样蛋白之间的关联性比非携带者更大 运营商（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).