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

项目总结 阿尔茨海默病(AD)是一种神经退行性疾病，表现为进行性记忆丧失和 思考和行动的能力。尽管我们在病理学方面积累了三十年的知识 机制，400多项针对病理通路的药物临床试验在很大程度上未能减少 认知能力下降。来自流行病学、神经影像和临床报告的最新证据表明 血管的贡献在AD的发病机制中起着关键作用。脑血流量(CBF)的减少 在临床前AD人群中被发现，在症状出现和观察到的多年之前 大脑的结构性萎缩。同时，血管病理生理学与较低的AD阈值有关 认知衰退和痴呆症的病理学。先前血管改变的特征可以提供 AD早期诊断和治疗评估的新机遇。然而，目前在体内 磁共振成像(MRI)和功能磁共振成像(FMRI)等神经成像工具专门专注于 大血管，由于其分辨率和敏感性有限，而大部分离开微血管领土 未被开发的。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 微静脉可以贡献超过50%的fMRI信号和微血管结构的改变 人类大脑的深刻功能变化。尽管它对神经退行性疾病有耐人寻味的见解， 这些模型要么基于过于简化的血管几何学，要么基于源自 ~1mm3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在 人类的大脑。这项研究的目标是建立一种多尺度光学成像技术来解开 人脑中的微血管构筑网络从单个毛细血管水平到数十立方厘米的 组织块。双光子串联切片光学相干层析成像系统的旋转 显微镜，多尺度成像技术利用高通量和彻底的血管系统研究 阿尔茨海默病进展的病理生理学。这项研究将重建人脑中的体积结构网络 在AD不同阶段的组织，寻找重要的特征来表征血管的病理变化， 并与定量神经病理评估相关联，了解AD病理的趋同路径 在疾病发展的过程中。随着基于成像的人脑微血管网络的建立， 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。这一计算框架已经使用微血管进行了验证 来自小动物模型的解剖学和动力学，这里我们第一次将其扩展到人类大脑皮层。 该项目的完成将极大地促进我们对微血管结构作用的理解 在AD进展中发挥作用，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.