PET imaging for neuroimmune function in Alzheimer's disease

项目摘要。预期寿命的增加大大增加了阿尔茨海默病(AD)的发病率 以及这种疾病给社会带来的经济负担。目前，还没有有效的治疗方法来治疗 阻止或逆转AD进程，这部分归因于缺乏翻译的跨物种生物标记物 既适用于临床前疾病模型，也适用于人类，便于药物发现和开发过程。 因此，开发可翻译的成像生物标记物用于非侵入性评估疾病进展和 治疗效果有望填补这一紧迫而未得到满足的临床需求的空白。 越来越多的证据表明，神经免疫功能的改变在AD的病理生理学早期就发生了。 在这里，我们建议使用一种新的成像策略来监测先天免疫功能，神经炎症， 以及AD治疗中新的AD治疗反应。该策略涉及到使用特定的正电子发射。 断层扫描(PET)示踪剂[18F]PF-974靶向cAMP依赖的环磷酸二酯酶亚型4B(PDE4B)。 因为cAMP是小胶质细胞内稳态的关键调节因子，而其他PDE4亚型通常与 作为cAMP信号的主要负调制子，PDE4B代表着一种 有望替代神经免疫功能和神经炎症的生物标志物。 PDE4B的表达和活性受脑部炎症的调节，反过来，PDE4B的变化反映了 改变了神经免疫功能。[18F]PF-974是唯一经过验证的PDE4B PET示踪剂，具有优异的结合亲和力和 与其他PDE4异构体和任何其他主要CNS靶标相比，对PDE4B具有高选择性。PET成像 对[18F]PF-974的评估证实，最近在非人灵长类动物的大脑中存在高特异性结合 翻译成人类。PI和他的团队是第一个评估[18F]PF-脑动力学和特异性结合的小组。 974在幼稚和神经炎症小鼠模型中的作用。我们的初步研究表明，示踪剂可以检测到 在脂多糖诱导的(急性和亚慢性)神经炎症小鼠模型中，神经炎症反应良好。 与我们的免疫组织学和病理结果相关联。到目前为止，没有直接的非侵入性 检测PDE4B在各种AD疾病中的分布和表达 [18F]PF-974-PET研究先天免疫功能的知识差距和机会因此，作为我们的具体行动， 目的：利用非侵入性的[18F]PF-974-PET，我们建议直接监测PDE4B在大脑中的变化作为一种 AD的神经炎症指数，并评估以CSF1R为靶向的新型AD疗法的治疗反应 通过生物验证。在此之后，我们的长期目标是评估[18F]PF-974-PET作为一种翻译 生物标志物在阿尔茨海默病病理生理和疗效评价中的应用 AD新药临床试验中的反应。

Project Summary. Increases in life expectancy have greatly increased the frequency of Alzheimer’s disease (AD) and the economic burden on society the disease entails. At present, there are no efficacious therapies available to halt or reverse AD progression, which is attributed to, in part, the lack of translational cross-species biomarkers suitable in both preclinical disease models and humans to facilitate drug discovery and development process. Therefore, development of translatable imaging biomarkers for non-invasive assessment of disease progression and therapeutic efficacy hold promises to fill the gap of this urgent and unmet clinical need. Growing evidence indicates altered neuroimmune function disruption occurs early in the AD pathophysiology. Herein we propose the use of a novel imaging strategy for monitoring innate immune function, neuroinflammation, and novel AD treatment response in AD therapy. The strategy involves the use of a specific positron emission tomography (PET) tracer [18F]PF-974 targeting cAMP-dependent cyclic phosphodiesterase subtype 4B (PDE4B). Because cAMP is a critical regulator of microglia homeostasis, while other PDE4 isoforms are often associated with debilitating adverse effects, PDE4B, as the predominant negative modulator for cAMP signaling, represents a promising surrogate biomarker for neuroimmune function and neuroinflammation. PDE4B expression and activity is regulated by inflammation in the brain, and in turn, PDE4B changes reflect altered neuroimmune function. [18F]PF-974 is the only validated PDE4B PET tracer with excellent binding affinity and high selectivity towards PDE4B over other PDE4 isoforms as well as any other major CNS targets. PET imaging evaluation of [18F]PF-974 confirmed high specific binding in the brain of nonhuman primates, which was recently translated to human. The PI and his team are the first group to evaluate brain kinetic and specific binding of [18F]PF- 974 in naïve and neuroinflammation mouse models. Our preliminary studies have shown that the tracer can detect neuroinflammation in LPS-induced (acute and subchronic) neuroinflammation mouse models, which was well- correlated with our immunohistological and pathological findings. To date, there is no direct non-invasive measurement of the distribution and expression of PDE4B in various AD disease, representing a substantial knowledge gap and opportunity to study innate immune function by [18F]PF-974-PET. Therefore, as our specific objectives, utilizing non-invasive [18F]PF-974-PET, we propose to directly monitor PDE4B changes in the brain as an index of neuroinflammation in AD, and evaluate treatment response for novel CSF1R-targeted AD therapies, followed by biological validation. Following this, our long-term goal is to assess the utility of [18F]PF-974-PET as a translational biomarker to provide new information of neuroimmune function in AD pathophysiology and to evaluate treatment response in clinical trials of novel AD drugs.