PET imaging for neuroimmune function in Alzheimer's disease

PET 成像研究阿尔茨海默病的神经免疫功能

基本信息

批准号：
10474697
负责人：
Steven H Liang
金额：
$ 43.04万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474697
关键词：
AD transgenic mice APP-PS1 Abeta synthesis Acute Adverse effects Affinity Alzheimer&apos s Disease Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid beta-Protein Anti-Inflammatory Agents Binding Biological Biological Markers Biological Process Brain CSF1R gene Characteristics Clinical Clinical Trials Cyclic AMP Development Disease Disease Progression Disease model Drug Targeting Early Intervention Economic Burden Frequencies Functional disorder Goals Homeostasis Human Image Image Analysis Imaging Device Immune Incidence Inflammation Kinetics Knowledge Life Expectancy Ligands Measurement Microglia Monitor Mus Neurodegenerative Disorders Neuroimmune Outcome Pathologic Periodicity Pharmaceutical Preparations Phenotype Positron-Emission Tomography Process Protein Isoforms Role Scientific Advances and Accomplishments Signal Transduction Societies Surrogate Markers Symptoms Testing Therapeutic Intervention Time Tracer Translating Treatment Efficacy United States Validation Work base cell type cytokine design disease phenotype drug development drug discovery efficacious treatment imaging biomarker imaging study immune function indexing inhibitor innate immune function mouse model neuroinflammation nonhuman primate novel outcome prediction phosphoric diester hydrolase pre-clinical response treatment response

项目摘要

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.

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。以及该疾病给社会带来的经济负担，目前尚无有效的治疗方法。阻止或逆转 AD 进展，部分原因是缺乏翻译性跨物种生物标志物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和治疗功效有望填补这一紧迫且未满足的临床需求的空白。越来越多的证据表明，神经免疫功能破坏的改变发生在 AD 病理生理学的早期。在此，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、 AD治疗中的新型AD治疗反应策略涉及使用特定的正电子发射。断层扫描 (PET) 示踪剂 [18F]PF-974 靶向 cAMP 依赖性环状磷酸二酯酶亚型 4B (PDE4B)。因为 cAMP 是小胶质细胞稳态的关键调节因子，而其他 PDE4 亚型通常与 PDE4B 作为 cAMP 信号传导的主要负调节剂，代表着一种令人衰弱的副作用有前景的神经免疫功能和神经炎症替代生物标志物。 PDE4B 的表达和活性受大脑炎症的调节，反过来，PDE4B 的变化反映了 [18F]PF-974 是唯一经过验证的 PDE4B PET 示踪剂，具有出色的结合亲和力和与其他 PDE4 亚型以及任何其他主要 CNS 成像目标相比，对 PDE4B 具有高选择性。 [18F]PF-974 的评估证实了非人类灵长类动物大脑中的高特异性结合，这是最近 PI 和他的团队是第一个评估 [18F]PF- 的大脑动力学和特异性结合的小组。第974章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，效果良好迄今为止，还没有直接的非侵入性方法与我们的免疫组织学和病理学发现相关。测量 PDE4B 在各种 AD 疾病中的分布和表达，代表了实质性因此，通过 [18F]PF-974-PET 研究先天免疫功能的知识差距和机会。目标，利用非侵入性 [18F]PF-974-PET，我们建议直接监测大脑中 PDE4B 的变化，作为 AD 神经炎症指数，并评估新型 CSF1R 靶向 AD 疗法的治疗反应，然后在此之后，我们的长期目标是评估 [18F]PF-974-PET 作为转化药物的效用。生物标志物提供 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 药物临床试验中的反应。