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 以及疾病给社会带来的经济负担。目前，没有有效的治疗方法可用于 阻止或逆转AD进展，部分原因是缺乏跨物种生物标志物翻译 适用于临床前疾病模型和人类，以促进药物发现和开发过程。 因此，开发可翻译的成像生物标志物用于疾病进展的非侵入性评估， 治疗效果有望填补这一迫切和未满足的临床需求的差距。 越来越多的证据表明，改变的神经免疫功能破坏发生在AD的病理生理早期。 在此，我们提出了一种新的成像策略，用于监测先天免疫功能，神经炎症， 和AD治疗中的新的AD治疗反应。该策略涉及使用特定的正电子发射 靶向cAMP依赖性环磷酸二酯酶亚型4 B（PDE 4 B）的断层扫描（PET）示踪剂[18 F]PF-974。 由于cAMP是小胶质细胞稳态的关键调节因子，而其他PDE 4亚型通常与小胶质细胞稳态相关。 PDE 4 B作为cAMP信号传导的主要负调节剂，代表了一种使人衰弱的副作用， 有希望的神经免疫功能和神经炎症的替代生物标志物。 PDE 4 B的表达和活性受大脑炎症的调节，反过来，PDE 4 B的变化反映了 改变神经免疫功能[18F]PF-974是唯一经验证的PDE 4 B PET示踪剂，具有优异的结合亲和力， 对PDE 4 B的选择性高于其他PDE 4亚型以及任何其他主要CNS靶标。PET成像 对[18 F]PF-974的评价证实了在非人灵长类动物脑中的高特异性结合， 翻译成人类PI和他的团队是第一个评估大脑动力学和[18F]PF特异性结合的团队。 974在幼稚和神经炎症小鼠模型中。我们的初步研究表明，示踪剂可以检测到 LPS诱导的（急性和亚慢性）神经炎症小鼠模型中的神经炎症， 与我们的免疫组织学和病理学发现相关。到目前为止，还没有直接的非侵入性 PDE 4 B在各种AD疾病中的分布和表达的测量，代表了实质性的 通过[18 F]PF-974-PET研究先天免疫功能的知识差距和机会。作为我们的具体 目的，利用非侵入性[18F]PF-974-PET，我们建议直接监测脑中PDE 4 B的变化， AD神经炎症指数，并评估新型CSF 1 R靶向AD治疗的治疗反应， 通过生物学验证。在此之后，我们的长期目标是评估[18F]PF-974-PET作为转化的 生物标志物，以提供AD病理生理学中神经免疫功能的新信息并评估治疗 新型AD药物临床试验的反应。

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.