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

新型体积光学显微镜揭示大脑微血管结构及其在人类阿尔茨海默氏病功能神经影像中的作用

• 批准号: 10669745
• 负责人: Hui Wang
• 金额: $ 74.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669745
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Anatomy; Animal Model; Animals; Architecture; Arteries; Atrophic; Biophysics; Blood Vessels; Blood capillaries; Blood flow; Brain; Cerebral Amyloid Angiopathy; Cerebral cortex; Cerebrovascular Circulation; Cerebrum; Characteristics; Clinical; Clinical Data; Clinical Trials; Complex; Computer Models; Data; Dementia; Diameter; Disease; Disease Progression; Early Intervention; Epidemiology; Exhibits; Fiber; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Geometry; Goals; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Individual; Knowledge; Label; Lead; Length; Light; Link; Magnetic Resonance Imaging; Maps; Measurable; Measurement; Measures; Medial; Memory Loss; Methods; Microscopic; Microscopy; Microvascular Dysfunction; Modeling; Morphology; Multimodal Imaging; Mus; Myelin; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Optical Coherence Tomography; Optics; Oxygen; Pathogenesis; Pathologic; Pathology; Pathway interactions; Perfusion; Physiology; Play; Population; Prefrontal Cortex; Property; Records; Reporting; Resolution; Role; Sampling; Senile Plaques; Severity of illness; Signal Transduction; Slice; Structure; Symptoms; Techniques; Temporal Lobe; Testing; Therapeutic; Therapeutic Intervention; Thinking; Time; Tissues; Vascular Diseases; Veins; Work; arteriole; biophysical model; brain tissue; computer framework; deep learning; density; digital pathology; gray matter; hemodynamics; human disease; human tissue; in vivo; insight; meter; morphometry; network architecture; neuroimaging; neuropathology; novel; optical imaging; oxygen transport; pre-clinical; reconstruction; response; simulation; targeted therapy trials; targeted treatment; therapeutic target; tool; two photon microscopy; vascular contributions; venule; white matter

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.

项目概要 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 尽管我们在病理方面的知识积累了三十年，但我们的思维和行动能力。 机制方面，超过 400 项针对病理途径的药物临床试验基本上未能减少 流行病学、神经影像学和临床报告的最新证据表明。 血管的贡献在 AD 的发病机制中至关重要。 在症状出现和观察到的许多年前，临床前 AD 人群就已认识到这一点 与此同时，血管病理生理学与 AD 阈值降低有关。 认知能力下降和痴呆的病理学特征可能会导致认知能力下降和痴呆。 早期 AD 诊断和治疗评估的新机会然而，目前的体内研究。 磁共振成像 (MRI) 和功能性 MRI (fMRI) 等神经影像工具专门专注于 大血管，由于其有限的分辨率和灵敏度，而在很大程度上留下了微血管区域 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 小静脉可以贡献超过 50% 的 fMRI 信号，微血管结构的改变导致 尽管它对神经退行性疾病有着有趣的见解， 这些模型要么基于过于简化的血管几何形状，要么基于源自以下的解剖网络： ~1mm3 的小鼠大脑皮层，通常无法预测复杂的结构和血流动力学 该研究的目标是建立一种多尺度光学成像技术来解开人类大脑的谜团。 人脑中的微血管结构网络从单个毛细血管水平到数十立方厘米 旋转连续切片光学相干断层扫描与双光子相结合。 显微镜，多尺度成像技术利用对脉管系统的高通量和彻底研究 AD 进展的病理生理学研究将重建人脑的体积结构网络。 AD不同阶段的组织，寻找重要特征来表征血管病理改变， 并与定量神经病理学评估相关联，以了解 AD 病理学的汇聚路径 凭借人脑中基于成像的微血管网络的基础， 该研究将进一步建立计算模型来研究脑血流、氧合和功能磁共振成像 AD 进展期间的信号。该计算框架已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，在这里我们首次将其扩展到人类皮质。 该项目的完成将显着增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 早期干预和靶向治疗开辟新途径。