Novel Volumetric Optical Microscopy to Unravel Cerebral Microvascular Architecture and the Role in Functional Neuroimaging in Human Alzheimer's Disease

项目摘要 阿尔茨海默氏病（AD）是一种神经退行性疾病，表现为记忆的进行性丧失， 思考和行动的能力。尽管我们对病理学的认识积累了三十年， 机制，超过400个针对病理途径的药物临床试验在很大程度上未能减少 认知能力下降流行病学、神经影像学和临床报告的最新证据表明， 血管在AD的发病机制中起关键作用。脑血流量（CBF）减少， 在临床前AD人群中，在症状发作和观察到的 大脑结构性萎缩同时，血管病理生理学与AD的低阈值相关 认知能力下降和痴呆的病理学。先前的血管改变的特征可能提供了一个 为早期AD诊断和治疗评估提供了新的机会。然而，目前在体内 诸如磁共振成像（MRI）和功能性MRI（fMRI）的神经成像工具专门关注 大血管，由于其有限的分辨率和灵敏度，而大部分微血管区域 未开发的我们的生物物理模拟工作和其他研究表明，毛细血管，小动脉 微静脉和小静脉可以提供超过50%的fMRI信号，微血管结构的改变导致 人类大脑的深刻功能变化。尽管它对神经退行性疾病有着有趣的见解， 这些模型要么是基于过于简化的血管几何结构，要么是基于 ~ 1 mm 3的小鼠大脑皮层，这往往无法预测复杂的结构和血流动力学， 人类的大脑该研究的目标是建立一种多尺度光学成像技术，以揭示 从单个毛细血管水平到数十立方厘米的微血管结构网络， 组织块双光子光学相干层析成像系统的旋转成像 显微镜，多尺度成像技术利用高通量和彻底的研究血管 AD进展的病理生理学。这项研究将重建人脑的体积结构网络 在AD的不同阶段的组织中，寻找表征血管病理学改变的重要特征， 并与定量神经病理学评估相关联，以了解AD病理学的会聚路径 在疾病进展期间。随着人类大脑中基于成像的微血管网络的建立， 这项研究将进一步建立一个计算模型来研究脑血流、氧合和功能磁共振成像。 AD进展过程中的信号。这一计算框架已得到验证，使用微血管 解剖学和动力学从小动物模型，在这里，我们第一次将其扩展到人类大脑皮层。 这个项目的完成将大大推进我们对微血管结构的作用的理解， 可能为AD的早期干预和靶向治疗开辟新的途径。

PROJECT SUMMARY Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests as progressive loss of memory and the ability in thinking and action. Despite thirty years accumulation of our knowledge on the pathological mechanisms, over 400 clinical trials of drugs targeting the pathological pathways have largely failed to reduce cognitive decline. Recent evidences from epidemiological, neuroimaging, and clinical reports have suggested that vascular contributions are critical in the pathogenesis of AD. A reduction of cerebral blood flow (CBF) has been recognized in preclinical AD population, many years before the onset of symptoms and the observed structural atrophy in the brain. In parallel, vascular pathophysiology is associated with a lower threshold of AD pathology in cognitive decline and dementia. The characteristic of preceding vascular alterations may offer a new opportunity in early-stage AD diagnosis and therapeutical assessment. However, current in vivo neuroimaging tools such as magnetic resonance imaging (MRI) and functional MRI (fMRI) exclusively focus on large vessels, due to their limited resolution and sensitivity, while leaving the microvascular territories largely unexplored. Our biophysical simulation work and other studies have indicated that capillaries, small arterioles and venules could contribute more than 50% of fMRI signals and alterations of microvascular architecture lead to profound functional changes in the human brain. Despite its intriguing insight on neurodegenerative diseases, those models were either based on oversimplified vascular geometry or anatomical networks derived from ~1mm3 of mouse cerebral cortex, which often failed to predict the complex architecture and hemodynamics in the human brain. The goal of the study is to establish a multiscale optical imaging technique to unravel the microvascular architecture network in the human brain from single capillary level to tens of cubic centimeters of tissue blocks. Pivoting on a serial sectioning optical coherence tomography combined with a two-photon microscopy, the multiscale imaging technique leverages a high-throughput and thorough study of vasculature pathophysiology in AD progression. The study will reconstruct volumetric architectural networks in human brain tissues at different stages of AD, seek for important features to characterize vascular pathological alterations, and correlate with quantitative neuropathological assessment to understand the converging path of AD pathology during disease progression. With the foundation of imaging-based microvascular networks in the human brain, the study will further build a computational model to investigate the cerebral blood flow, oxygenation, and fMRI signals during AD progression. This computational framework has been validated using the microvascular anatomy and dynamics from small animal models, and here we extend it for the first time to the human cortex. Completion of this project will significantly advance our understanding of the role microvascular architecture plays in AD progression that may open new avenues for early intervention and targeted therapy of AD.