Photoacoustic Microscopy of Metabolic Dysfunction in Alzheimer’s Disease

 描述(申请人提供)：阿尔茨海默病(AD)是导致成人残疾的主要原因，也是美国最常见的痴呆症原因。尽管人们已经做出了巨大的努力来了解阿尔茨海默病，但还没有找到治愈的方法。目前针对中枢神经系统的治疗显示出有限的疗效。新的证据表明AD的病理和共存的脑代谢功能障碍之间存在协同作用。然而，代谢功能障碍是一个潜在的原因，还是仅仅是疾病的结果，目前还不确定。回答这个问题可能会揭示针对AD代谢途径中断的新的、有望更有效的治疗方法。研究代谢功能障碍和AD病理之间的因果关系需要一种能够在时空上成像大脑代谢和淀粉样斑块沉积的技术--淀粉样斑块是AD的关键病理标志。正电子发射断层扫描(PET)可以在临床上完成这一任务；然而，斑块沉积的初始阶段在很大程度上是无症状的，因此很难在患者身上捕捉到。通过既定的基因改变概括AD病理的小鼠模型非常适合于这项机制研究，因为它们记录了斑块发展的时间表。此外，在小鼠AD模型中，局灶性缺血可以触发缺血皮质中淀粉样斑块的快速播种，而不是对侧的自发播种。这一范式提供了一个独特的机会来研究代谢障碍和AD病理之间的关系，在诱导和自发斑块发展在同一小鼠。虽然令人兴奋，但对小鼠个别斑块的出现和局部大脑新陈代谢的破坏进行成像需要比PET高得多的空间分辨率。光声显微镜(PAM)具有很大的潜力来满足这一技术需求。在这项拟议的研究中，将开发一种新的二色性对比剂，使单个淀粉样斑块的高对比度PAM能够透过完整的小鼠头骨。同时，将建立一种新的方法来计算AD小鼠大脑组织水平上的总血红蛋白浓度、血红蛋白的氧饱和度、氧提取分数和脑血流量。通过这四个组织水平的测量，可以在微观水平上计算出大脑的氧代谢率-一个金标准的代谢指标。将淀粉样蛋白和代谢对比整合到一个前所未有的PAM平台中，最终将使我们能够在相同的时空尺度上成像AD的病理和代谢功能障碍。在小鼠AD缺血模型中，PAM获得的CMRO2和淀粉样蛋白聚集的共同进化将不可能通过聚集的观察从不同的时空尺度上操作的不同成像技术的集合中获得。这一技术创新将为AD代谢途径的机制研究开辟一条新的途径，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.