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联

• 批准号: 10469657
• 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/10469657
• 关键词: Age; 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; Disease; Disease Progression; Edema; Elderly; Ensure; Episodic memory; Evolution; Excision; Fiber; Functional disorder; Genetic Risk; Guidelines; Health; 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; Symptoms; Synapses; Temporal Lobe; Testing; Time; aging population; base; blood-brain barrier disruption; blood-brain barrier permeabilization; cerebral atrophy; cerebrovascular; cognitive function; contrast enhanced; density; follow-up; gray matter; improved; in vivo; mild cognitive impairment; molecular marker; molecular pathology; morphometry; neuroimaging; neuropathology; neurovascular; normal aging; pre-clinical; prodromal Alzheimer' s disease; relating to nervous system; 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：随着认知能力下降是我们老龄化人口日益关注的健康问题，它正在成为 更好地描述导致年龄相关认知的神经生物学变化日益重要 损伤和痴呆症。尽管神经成像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 提高了对疾病最早阶段的敏感性，那时的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， 并可能先于脑萎缩。需要进一步的研究来了解血脑屏障通透性是如何变化的 在阿尔茨海默病的病程中，以及它与脑微结构、形态计量学和已建立的脑微结构标志物之间的关系 分子病理学。 初步研究：我们的初步研究显示限制光谱成像(RSI)对 轻度认知障碍(MCI)和早期AD的脑微结构改变RSI、认知功能和 对31例健康对照(HC)、12例轻度脑梗塞和13例轻度AD患者的脑脊液淀粉样蛋白β进行了检测。 轴突密度(ND)，一种限制水扩散的指标，解释了交叉纤维，在 MCI/AD组较HC组多条白质束、灰质各向同性自由水弥散(IF)值高。 ND和IF与情景记忆和淀粉样蛋白-β负荷相关。 建议的研究：动态增强磁共振成像、核磁共振成像、结构磁共振成像、脑脊液淀粉样蛋白-β和tau，以及 神经心理学数据将在遗传风险较低的AD(APOE4非携带者)15个HC和15个HC上获得 患有MCI的个体。血脑屏障渗透率将在不同组之间进行比较，并与记忆相关 表现、RSI测量、形态测量和淀粉样蛋白/tau，以测试血脑屏障损伤是否与 有微结构改变、认知障碍和已建立的AD生物标志物 AD(目标1)。在R00阶段，神经影像、脑脊液和认知数据将在40HC和LOW上收集 AD的遗传风险，70名阿尔茨海默病(APOE4携带者)遗传风险升高的HC和70名MCI患者。全 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分解和RSI指标预测认知能力下降，并对临床前AD敏感(Aim 2A)。 来自所有阶段的数据将被组合在一起，以模拟血脑屏障通透性、大脑 从正常到前驱阿尔茨海默病的微观结构和分子病理学(目标2B)。淀粉样蛋白PET将成为 对一部分参与者(31名淀粉样阴性HC，37名淀粉样阳性HC，31名MCI)进行测试 假设血脑屏障的破坏与淀粉样蛋白沉积相关并共同定位，并且 APOE4携带者血脑屏障通透性增加与淀粉样蛋白的相关性比非携带者更大 承运人(目标3)。