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: 9262156
• 负责人: Song Hu
• 金额: $ 19.16万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262156
• 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; Chlorides; Clinic; Clinical; Collection; Complex; Congo Red; Contralateral; Dementia; Dependence; Deposition; Development; Disease; Disease Progression; Employee Strikes; Environment; Etiology; Evolution; Functional disorder; Genetic; Gold; 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; Pathogenicity; Pathologic; Pathology; Patients; Positron-Emission Tomography; Preparation; Property; Research; Resolution; Role; Senile Plaques; Side; Slice; Specificity; Staining method; Stains; Techniques; Testing; Time; TimeLine; Tissues; United States; amyloid imaging; base; brain metabolism; cranium; dichroism; disability; effective therapy; in vivo; indexing; innovation; metabolic abnormality assessment; metabolic rate; mouse model; novel; public health relevance; serial imaging; 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（由申请人提供）：阿尔茨海默氏病 (AD) 是导致成人残疾的主要原因，也是美国痴呆症的最常见原因，尽管人们在了解 AD 方面付出了巨大的努力，但目前尚未找到针对该疾病的治疗方法。新的证据表明 AD 病理学与共存的脑代谢功能障碍之间存在协同作用，但仍不确定代谢功能障碍是否是根本原因或仅仅是疾病的结果。阐明针对 AD 中被破坏的代谢途径的新且有望更有效的疗法 检查代谢功能障碍与 AD 病理之间的因果关系需要一种能够对大脑代谢和淀粉样斑块沉积进行时空成像的技术，这是 AD 的关键病理标志。 (PET) 可以在临床上完成这项任务；然而，斑块沉积的初始阶段基本上是无症状的，因此很难通过已确定的基因改变来重现 AD 病理学的小鼠模型。非常适合这项机制研究，因为他们已经记录了斑块发展的时间表，此外，小鼠 AD 模型中的局灶性缺血可以触发缺血皮质中淀粉样斑块的快速播种，这与对侧的自发播种相反。这是研究同一只小鼠诱导和自发斑块发展中代谢功能障碍与 AD 病理之间关系的独特机会，尽管令人兴奋，但对小鼠中单个斑块的出现和局部脑代谢破坏进行成像需要远远超出这一范围的高空间分辨率。的PET.光声显微镜（PAM）在满足这一技术需求方面具有巨大的潜力，在拟议的研究中，将开发一种新的二色性对比度，以通过完整的小鼠头骨实现单个淀粉样蛋白斑块的高对比度PAM。将建立 AD 小鼠大脑组织水平的血红蛋白总浓度、血红蛋白氧饱和度、氧提取分数和脑血流量。将淀粉样蛋白和代谢对比整合到前所未有的 PAM 平台中，最终使我们能够在 CMRO2 的相同时空尺度上对 AD 病理学和代谢功能障碍进行成像。否则，通过在不同时空操作的不同成像技术的集合的聚集观察，不可能获得小鼠 AD 缺血模型中 PAM 获得的淀粉样蛋白聚集这项技术创新将为 AD 中被破坏的代谢途径的机制研究开辟一条新途径，这可能会带来新颖且有前途的治疗方法。