脉冲聚焦超声辅助磁共振靶向纳米探针β淀粉样蛋白成像在阿尔茨海默病的精确定量研究

Alzheimer’s Disease (AD) is the 6th leading cause of death in aged population without an effective method to prevent，cure or even slow down the disease. Amyloidosis and neurodegeneration are hallmarks in AD. In spite of the recent failures of amyloid clearing drugs in AD，there still remains a need to understand the pathophysiology of brain Aβ deposition. In research settings，PET is increasingly used in humans to map Aβ deposits in AD. However，the Amyloid PET is limited by the low spatial resolution and partial volume effect from non-specific white matter bindings. it is unclear whether this modality will enable the routine detection of the earliest stages of Aβ deposits. Conversely，MRI has a much higher spatial resolution than PET and is superior for assessment of the whole brain. Aβ specific ligands with paramagnetic tags offered a promising solution with high sensitivity. We received USPIO-PEG-Aβ1-42 particles from NYU medical center，and combined with the application of pulsed focused ultrasound (FUS) associated with the intravenous injection of microbubbles is an efficient noninvasive way to disrupt the blood–brain barrier to deliver the MRI contrast. We will establish the best experimental conditions for the blood–brain barrier permeation and evaluate the duration of the window in which the mouse brain remains open using Gadolinium-based paramagnetic MRI agent. We hypothesize that our FUS targeting approach based on MRI-tagged nano-probes will map Aβ plaques with high sensitivity and specificity and enable its use for the detection of AD pathology, comparable with the immunolabeled tissue sections. These experiments will provide critical data to help establish MRI as an alternative tool to effectively monitor the amyloidosis.

阿尔茨海默病（AD）是社会老龄化面临的严重问题，是老年人第六大死亡原因。研究发现脑内β淀粉样蛋白（Aβ）斑块是AD标志性病理改变和治疗研究靶区之一。目前AD特异性诊断和早期干预效果的影像学依据主要依赖正电子发射断层扫描Aβ成像，但是该检查方法空间分辨率和检测精细程度低，价格昂贵，限制了临床应用。磁共振技术具有良好空间分辨率，磁共振靶向纳米探针使该技术应用达到分子水平，但是MRI纳米探针不能有效透过血脑屏障。本研究采用脉冲聚焦超声与微气泡技术，提高动物模型血脑屏障的通透性，利用新型Aβ特异性标记的纳米探针对Aβ斑块进行特异性显像，对照免疫组化结果，定量分析该特异性纳米探针在动物模型中检测Aβ斑块的准确性，为AD早期诊断及新疗法的治疗效果评估提供理论依据。

阿尔茨海默病（AD）是社会老龄化面临的严重问题，是老年人第六大死亡原因。研究发现 脑内β淀粉样蛋白（Aβ）斑块是AD标志性病理改变和治疗研究靶区之一。目前AD特异性诊断和早期干预效果的影像学依据主要依赖正电子发射断层扫描Aβ成像，但是该检查方法空间分辨率和检测精细程度低，价格昂贵，限制了临床应用。磁共振技术具有良好空间分辨率，磁共振靶向纳米探针使该技术应用达到分子水平，但是MRI纳米探针不能有效透过血脑屏障。本研究采用脉冲聚焦超声技术，提高动物模型血脑屏障的通透性，利用新型Aβ特异性标记的纳米探针对Aβ斑块进行特异性显像，对照免疫组化结果，定量分析该特异性纳米探针在动物模型中检测Aβ斑块的准确性。.本研究建立了性能稳定的超声刺激系统，设计合适的换能器及准直系统适用于小鼠大脑进行聚焦超声刺激，通过脑电信号检测，验证了超声刺激对脑功能的影响。通过对照聚焦超声和聚焦超声联合微泡对小鼠血脑屏障的影响，发现仅依靠一定强度的超声也能够产生与文献中聚焦超声联合微泡对血脑屏障的影响效果，减少了聚焦超声的应用限制。研究证实USPIO-PEG-Aβ1-42 纳米探针对AD小鼠Aβ斑块的结合能力，为纳米探针对AD的检测应用提供了理论依据。.