Photoacoustic Microscopy of Metabolic Dysfunction in Alzheimer’s Disease

 描述（由申请人提供）：阿尔茨海默病（AD）是美国成人残疾的主要原因，也是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，但还没有找到治愈AD的方法。目前针对中枢神经系统的治疗方法显示出有限的疗效。新出现的证据表明，AD病理学和脑代谢中共存的功能障碍之间存在协同效应。然而，代谢功能障碍是疾病的根本原因还是仅仅是疾病的结果仍然不确定。探讨这个问题可能会揭示新的，希望更有效的治疗方法，目标是破坏代谢途径的AD。检查代谢功能障碍和AD病理之间的因果关系，需要一种技术，能够时空成像脑代谢和淀粉样斑块的沉积-AD的一个关键的病理标志。正电子发射断层扫描（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，因此难以在患者中捕获。通过已建立的遗传改变再现AD病理的小鼠模型非常适合于这种机制研究，因为它们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触发缺血皮质中淀粉样蛋白斑块的快速播种，与对侧的自发播种相反。这种模式提供了一个独特的机会，研究代谢功能障碍和AD病理学之间的关系，在同一只小鼠诱导和自发斑块的发展。虽然令人兴奋，但对小鼠个体斑块的外观和局部脑代谢的破坏进行成像需要远远超过PET的高空间分辨率。光声显微镜（PAM）具有很大的潜力，以满足这一技术需求。在拟议的研究中，将开发一种新的二色性对比度，以使单个淀粉样蛋白斑块的高对比度PAM通过完整的小鼠头骨。与此同时，将建立一种新的方法来推导AD小鼠脑中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。通过这四个组织水平的测量，大脑的氧代谢率--一个金标准的代谢指标--可以在微观水平上计算出来。将淀粉样蛋白和代谢对比整合到前所未有的PAM平台中，最终将使我们能够在相同的时空尺度上对AD病理和代谢功能障碍进行成像。在小鼠AD-缺血模型中通过PAM获得的CMRO 2和淀粉样蛋白聚集的共同进化否则将不可能通过来自在不同时空尺度下操作的不同成像技术的集合的聚集观察来获得。这一技术创新将为AD中代谢途径中断的机制研究开辟新的途径，这可能导致新的和有前途的治疗方法。

 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.