Photoacoustic Microscopy of Metabolic Dysfunction in Alzheimer’s Disease

阿尔茨海默病代谢功能障碍的光声显微镜

• 批准号: 9019455
• 负责人: Song Hu
• 金额: $ 23.16万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9019455
• 关键词: APP-PS1; Address; Adult; Algorithms; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid deposition; Appearance; Blood Vessels; Brain; Cerebrovascular Circulation; Cerebrum; Chloride Ion; Chlorides; Clinic; Clinical; Collection; Complex; Congo Red; Contralateral; Dementia; Dependence; Deposition; Development; Disease; Disease Progression; Employee Strikes; Environment; Etiology; Evolution; Functional disorder; Genetic; Gold; Health; Hemoglobin; Image; Imaging Techniques; Incidence; Individual; Infarction; Ischemia; Lead; Light; Maps; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Methodology; Microscopic; Microscopy; Middle Cerebral Artery Occlusion; Modeling; Monitor; Mus; Mutation; Nerve Degeneration; Neuraxis; Noise; Oxygen; Pathogenesis; Pathology; Patients; Positron-Emission Tomography; Preparation; Property; Research; Resolution; Role; Senile Plaques; Side; Slice; Specificity; Staging; Staining method; Stains; Techniques; Testing; Time; TimeLine; Tissues; United States; base; brain metabolism; cranium; dichroism; disability; effective therapy; in vivo; indexing; innovation; meetings; metabolic abnormality assessment; metabolic rate; mouse model; novel; spatiotemporal; targeted treatment; therapeutic target; transmission process

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a leading cause of adult disability and the most common cause of dementia in the United States. Although tremendous efforts have focused on understanding AD, no cure has been found. Current therapies that target the central nervous system show limited efficacy. Emerging evidence suggests a synergistic effect between AD pathology and the coexisting dysfunction in cerebral metabolism. However, it is still uncertain whether the metabolic dysfunction is an underlying cause or merely a consequence of disease. Answering this question may shed light on new and hopefully more effective therapies that target disrupted metabolic pathways in AD. Examining the causality between metabolic dysfunction and AD pathology requires a technique capable of spatiotemporally imaging both cerebral metabolism and the deposition of amyloid plaques-a key pathological hallmark of AD. Positron emission tomography (PET) can carry out this task in the clinic; however, the initial stage of plaque deposition is largely asymptomatic and thus difficult to capture in patients. Mouse models that recapitulate AD pathology through established genetic alterations are ideally suited for this mechanistic study, because they have documented timelines of plaque development. Moreover, focal ischemia in mouse AD models can trigger rapid seeding of amyloid plaques in the ischemic cortex, in contrast to the spontaneous seeding on the contralateral side. This paradigm offers a unique opportunity to study the relationship between metabolism dysfunction and AD pathology in both induced and spontaneous plaque development in the same mouse. Although exciting, imaging the appearance of individual plaques and the disruption of local cerebral metabolism in mice requires high spatial resolution far beyond that of PET. Photoacoustic microscopy (PAM) holds great potential to meet this technical demand. In the proposed research, a novel dichroism contrast will be developed to enable high-contrast PAM of individual amyloid plaques through the intact mouse skull. In parallel, a new methodology will be established to derive total concentration of hemoglobin, oxygen saturation of hemoglobin, oxygen extraction fraction, and cerebral blood flow at the tissue level in the AD mouse brain. With the four tissue- level measurements, the cerebral metabolic rate of oxygen-a gold-standard metabolic index-can be computed at the microscopic level. Integrating the amyloid and metabolic contrasts into an unprecedented PAM platform will ultimately enable us to image AD pathology and metabolic dysfunction at the same spatiotemporal scale. The co-evolution of CMRO2 and amyloid aggregation acquired by PAM in the mouse AD-ischemia model would otherwise be impossible to obtain with agglomerated observations from a collection of different imaging techniques operating at different spatiotemporal scales. This technical innovation will open a new avenue for mechanistic studies of the disrupted metabolic pathways in AD, which may lead to novel and promising therapies.

 描述（由适用提供）：阿尔茨海默氏病（AD）是成人残疾的主要原因，也是美国痴呆症最常见的原因。尽管巨大的努力集中在理解AD上，但尚未发现治愈。针对中枢神经系统的当前疗法显示有效性有限。新兴的证据表明，AD病理学与脑代谢中共存功能障碍之间具有协同作用。但是，仍然不确定代谢功能障碍是根本原因还是仅仅是疾病的结果。回答这个问题可能会阐明新的，希望更有效的疗法针对AD中的代谢途径中断。检查代谢功能障碍和AD病理学之间的因果关系需要一种能够在空间成像大脑代谢和淀粉样蛋白plaques-A关键病理标志性标志性发射断层扫描（PET）的技术可以在临床中执行这项任务；但是，牙菌斑沉积的初始阶段在很大程度上是不对称的，因此在患者中很难捕获。通过既定的遗传改变概括AD病理的小鼠模型非常适合这项机械研究，因为它们已经记录了牙菌斑发育的时间表。此外，与对侧侧的赞助相反，小鼠AD模型中的局灶性缺血可以触发缺血性皮层中淀粉样蛋白斑块的快速播种。该范式提供了一个独特的机会，可以在同一小鼠的诱导和赞助牙菌斑发展中研究代谢功能障碍与AD病理学之间的关系。虽然令人兴奋，但要想成像单个斑块的外观以及小鼠中局部大脑代谢的破坏需要高空间分辨率，远远超出了宠物。光声显微镜（PAM）具有满足这一技术需求的巨大潜力。在拟议的研究中，将开发出一种新型的二分性对比，以通过完整的小鼠头骨使单个淀粉样板的高对比度PAM。同时，将建立一种新的方法，以导致血红蛋白的总浓度，血红蛋白的氧饱和度，氧气提取分数以及AD小鼠大脑组织的组织水平的脑血流。通过四个组织水平的测量，在微观水平上计算氧气A-A-A金标准代谢指数-CAN的大脑代谢率。将淀粉样蛋白和代谢对比度整合到前所未有的PAM平台中，最终将使我们能够在相同的时空量表上对AD病理学和代谢功能障碍进行图像。 PAM在小鼠Ad-Ischemia模型中获得的CMRO2和淀粉样蛋白聚集的共同进化否则将无法通过从不同时空尺度上运行的不同成像技术的集聚观测来获得。这项技术创新将为AD中破坏的代谢途径的机械研究开辟新的途径，这可能会导致新颖和承诺的疗法。