Dual-modal ultrasound velocimetry and photoacoustic oximetry of entire rodent brain for Alzheimer's Disease study

用于阿尔茨海默病研究的整个啮齿动物大脑的双模超声测速和光声血氧测定

• 批准号: 9976042
• 负责人: Jianbo Tang
• 金额: $ 11.52万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2020-10-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976042
• 关键词: AD transgenic mice; Algorithms; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Amyloid; Award; Behavioral; Blood Flow Velocity; Blood capillaries; Boa; Boston; Brain; Brain Diseases; Brain imaging; Brain region; Cerebral cortex; Cerebrovascular Circulation; Cerebrum; Communication; Data; Deposition; Development; Disease Progression; Environment; Event; Evolution; Goals; Grant; Hemoglobin; Hippocampus (Brain); Image; Imaging Techniques; Imaging technology; Impairment; Interdisciplinary Study; Interview; Investigation; Knowledge; Laboratories; Lead; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Memory; Mentors; Methods; Microbubbles; Microscopy; Modality; Morphology; Mus; Nerve Degeneration; Neurosciences; Neurosciences Research; Optical Coherence Tomography; Optics; Outcome; Oxygen; Oxygen saturation measurement; Penetration; Phase; Program Development; Research; Research Personnel; Resolution; Rodent; Structure; System; Technology; Testing; Thalamic structure; Theoretical model; Time; Tissues; Training; Ultrasonography; Universities; Validation; Vascular Diseases; Velocimetries; Writing; acoustic imaging; aging brain; algorithm development; base; bioimaging; blood flow measurement; bulk motion; career development; cerebral hemodynamics; cerebrovascular; computerized data processing; experience; hemodynamics; imaging modality; improved; in vivo; in vivo imaging; metabolic rate; mouse model; neuropathology; neurovascular; neurovascular coupling; novel; novel imaging technology; optical imaging; optoacoustic tomography; pre-clinical; preclinical study; programs; reconstruction; relating to nervous system; serial imaging; skills; spatiotemporal; submicron; tau Proteins; technology development; temporal measurement

Project Summary/Abstract The progression of Alzheimer’s Disease (AD) appears to initially take place in the hippocampus where memory is formed. Recent studies have demonstrated that impaired neurovascular uncoupling and capillary flow abnormalities precede neurodegeneration and that AD neuropathology is associated with dysregulation of the cerebral circulation and alteration of microvasculature morphology. In vivo imaging of cerebral blood flow (CBF), oxygen saturation (SO2), and cerebral metabolic rate of oxygen (CMRO2) not just in the cortical but also in the subcortical regions is thus of critical importance to study vascular dysfunction during AD progression. Currently available imaging methods are limited either by shallow penetration which only allows imaging superficial cortical layers (eg. optical imaging) or by low spatiotemporal resolution (eg. MRI and CT). The ability to bring together the functional and structural information from a large field-of-view, at a high spatiotemporal resolution would permit new preclinical studies advancing our understanding of the healthy and diseased brain. The goal of this K99/R00 proposal is to develop a novel ultrasound velocimetry and integrate it with photoacoustic oximetry for CBF, SO2, and CMRO2 imaging of the entire rodent brain with ~100 micron-sub second spatiotemporal resolution. Specifically, in Aim 1, the candidate will develop an ultrasound speckle decorrelation- based velocimetry (vUS) for quantitative CBF imaging; in Aim 2, the candidate will implement a multispectral photoacoustic tomography (mPAT) for SO2 and integrate the vUS and mPAT to measure CMRO2. The proposed K99/R00 program will focus on applying the technology to investigate Aim 3: Alzheimer’s disease (AD) in a triple transgenic AD mouse model. The outcome of Aim 3 will improve our understanding of the different time courses of hemodynamics and oxygenation changes, and the cause-and-effect relationship between cerebrovascular alterations and AD neuropathology during the disease progression. The proposed research will be conducted at the BOAS lab/Neurophotonics Center at Boston University, which is an ideal environment for developing biomedical imaging technology and applying it to neuroscience research. A strong mentoring team has been formed by the candidate which includes Dr. David Boas, a pioneer in applying optic imaging for neuroscience study, Dr. Thomas Szabo, an expert in ultrasound technology, Dr. Anna Devor, who has extensive experience in neurovascular coupling and neural imaging, and Dr. Benjamin Wolozin who is an expert in the field of neurodegenerative mechanism and treatment. Through this proposed K99/R00 research and professional development program, the candidate will receive didactic training in AD related neurodegeneration and brain imaging technology development, and also strengthen skills in planning, communication, interviewing, grant writing and laboratory management. By fulfilling the aims, the candidate will be well equipped to become an independent investigator and lead an inter-disciplinary research program.

项目总结/摘要 阿尔茨海默病（AD）的进展似乎最初发生在海马体中， 形成有最近的研究表明，受损的神经血管解偶联和毛细血管流动 AD神经病理学与神经退行性变之前的异常有关，并且AD神经病理学与神经退行性变的调节异常有关。 脑循环和微血管形态学改变。脑血流（CBF）的体内成像， 氧饱和度（SO2）和大脑氧代谢率（CMRO 2）不仅在皮层，而且在大脑皮层。 因此，皮质下区域对于研究AD进展期间的血管功能障碍至关重要。目前 可用的成像方法受到仅允许对表面皮层成像的浅穿透的限制 层（例如，光学成像）或通过低时空分辨率（例如，MRI和CT）。能够将 在高时空分辨率下，来自大视场的功能和结构信息将 允许新的临床前研究推进我们对健康和患病大脑的了解。 这个K99/R 00提案的目标是开发一种新的超声测速仪，并将其与光声集成 血氧饱和度测定，用于整个啮齿动物大脑的CBF、SO2和CMRO 2成像，约100微米亚秒 时空分辨率具体而言，在目标1中，候选人将开发超声散斑去相关- 用于定量CBF成像的基于速度测量（vUS）;在目标2中，候选人将实施多光谱 光声断层扫描（mPAT）的SO2和整合vUS和mPAT测量CMRO 2。拟议 K99/R 00计划将专注于应用该技术以三重方式研究Aim 3：阿尔茨海默病（AD） 转基因AD小鼠模型。目标3的结果将增进我们对不同时间进程的理解 血流动力学和氧合的变化，以及脑血管疾病之间的因果关系 改变和AD神经病理学在疾病进展过程中。 拟议的研究将在波士顿大学的BOAS实验室/神经光子学中心进行， 是发展生物医学成像技术并将其应用于神经科学研究的理想环境。 候选人组建了一个强大的指导团队，其中包括申请的先驱大卫博厄斯博士。 神经科学研究的光学成像，托马斯萨博博士，超声技术专家，安娜德沃尔博士， 他在神经血管耦合和神经成像方面拥有丰富的经验，本杰明·沃洛津博士， 神经变性机制和治疗领域的专家。通过K99/R 00研究 和专业发展计划，候选人将接受广告相关的教学培训 神经变性和脑成像技术的发展，并加强规划技能， 沟通，面试，授权书撰写和实验室管理。通过实现目标，候选人将 有能力成为一名独立的调查员，并领导一个跨学科的研究计划。