PET Imaging for neuroinflammation in Alzheimer's disease

阿尔茨海默病神经炎症的 PET 成像

• 批准号: 10653556
• 负责人: Steven H Liang
• 金额: $ 19.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10653556
• 关键词: AD transgenic mice; Abeta synthesis; Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Anti-Inflammatory Agents; Astrocytes; Behavioral; Binding; Biological; Biological Markers; Brain; CSF1R gene; Clinical; Clinical Trials; Development; Disease; Disease Progression; Disease model; Dose; Early Intervention; Evaluation; Functional disorder; Goals; Human; Image; Imaging Device; Immune; Incidence; Inflammation; Kinetics; Knowledge; Ligands; Measurement; Measures; Microglia; Modeling; Monitor; Neurodegenerative Disorders; Neuroimmune; Neurons; Outcome; Patients; Permeability; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Production; Rodent; Role; Scientific Advances and Accomplishments; Senile Plaques; Severities; Signal Transduction; Symptoms; Synapses; Testing; Therapeutic; Therapeutic Intervention; Time; Tracer; Translating; Treatment Efficacy; United States; Work; behavioral study; density; design; drug development; drug discovery; efficacious treatment; imaging biomarker; imaging study; in vivo; indexing; inhibitor; innate immune function; mouse model; neuroinflammation; nonhuman primate; novel; outcome prediction; pre-clinical; receptor; receptor binding; receptor expression; response; tau Proteins; treatment response

Project Summary 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 microglia and neuroimmune function disruption occurs early in the AD pathophysiology. We have also seen that early intervention against neuroinflammation could substantially impact the incidence and progression of AD. Herein we propose the use of a novel imaging strategy for monitoring innate immune function, neuroinflammation, and microglia-modulating treatment response in AD therapy. Our strategy involves the use of a specific positron emission tomography (PET) tracer [18F]JNJ-739 targeting purinergic P2X7 receptor (P2X7R). Increased P2X7R expression has been found in microglial cells surrounding amyloid plaques both in AD patients and different AD mouse models, which parallels with AD progression. [18F]JNJ-739 is the only validated P2X7R PET tracer that showed high permeability and specific binding in the brain of nonhuman primates and has recently translated to human use. The ligand possesses excellent binding affinity (IC50 1.0 nM) and high selectivity (>100 fold) towards any other major CNS targets. The PI and his team have evaluated brain kinetic and specific binding of [18F]JNJ-739 in neuroinflammation mouse models. Our preliminary studies have shown that [18F]JNJ-739-PET can detect and monitor neuroinflammation in LPS-induced neuroinflammation mouse models, which was well-correlated with our immunohistological findings. To date, there is no direct non-invasive in vivo measurement of the distribution and expression of P2X7R in various AD stages, representing a substantial knowledge gap and opportunity to study microglia activation and innate immune function by [18F]JNJ-739-PET. Our hypothesis entails that increased P2X7R brain binding, determined by [18F]JNJ-739-PET, is correlated with AD symptom severity, increased neuroinflammation, activated microglia and severe innate immune disruption, as well as high Aβ/tau production. Therefore, as our specific objectives, utilizing non-invasive [18F]JNJ-739-PET, we propose to directly monitor P2X7R changes in the brain as an index of neuroinflammation and altered microglia in AD, and determine target engagement. Following this, our long-term goal is to assess the utility of [18F]JNJ-739-PET as a translational biomarker to provide new information of AD pathophysiology and to evaluate treatment response in clinical trials of novel AD drugs.

项目摘要 没有有效的疗法可用于停止或反向AD进展，这部分归因于 缺乏适用于临床前疾病模型和人类的翻译跨物种生物标志物 促进药物发现和开发过程。因此，开发可翻译成像生物标志物 对于疾病进展和治疗效率的无创评估，有望填补这一空白 紧急且未满足的临床需求。越来越多的证据表明小胶质细胞和神经免疫功能改变了 破坏发生在AD病理生理学的早期。我们还看到，早期干预 神经炎症可能会大大影响AD的事件和进展。在此我们建议使用 一种新的成像策略，用于监测先天免疫功能，神经炎症和小胶质细胞调节 广告疗法中的治疗反应。我们的策略涉及使用特定的正电子发射断层扫描 （PET）示踪剂[18F] JNJ-739靶向嘌呤能P2X7受体（P2X7R）。 p2x7r表达的增加已经 在AD患者和不同AD小鼠模型的淀粉样蛋白斑块周围的小胶质细胞中发现，它们 与广告进展相似。 [18F] JNJ-739是唯一验证的P2X7R宠物示踪剂 非人类隐私的大脑中的渗透性和特定结合，最近已转化为人类使用。 配体具有出色的结合亲和力（IC50 1.0 nm）和高选择性（> 100倍） 主要中枢神经系统目标。 PI和他的团队评估了[18F] JNJ-739的大脑动力学和特定的结合 神经炎症小鼠模型。我们的初步研究表明，[18F] JNJ-739-PET可以检测和 监测LPS诱导的神经炎症小鼠模型中的神经炎症，该模型与 我们的免疫组织学发现。 迄今 各种广告阶段，代表了研究小胶质细胞激活和 先天免疫功能[18F] JNJ-739-PET。我们的假设需要增加p2x7r脑结合， 由[18F] JNJ-739-PET确定，与AD症状严重程度相关，神经炎症增加， 活化的小胶质细胞和严重的先天免疫中断以及高Aβ/TAU产生。因此，作为我们的 特定目标，使用非侵入性[18F] JNJ-739-PET，我们建议直接监视P2X7R的更改 大脑作为神经炎症的指数和AD中的小胶质细胞改变，并确定了靶标参与。 之后，我们的长期目标是评估[18F] JNJ-739-PET作为翻译生物标志物的实用性 提供AD病理生理学的新信息并评估新型AD临床试验中的治疗反应 毒品。

项目成果

Assessment of cholesterol homeostasis in the living human brain.

• DOI: 10.1126/scitranslmed.adc9967
• 发表时间: 2022-10-05
• 期刊: SCIENCE TRANSLATIONAL MEDICINE
• 影响因子: 17.1
• 作者: Haider, Ahmed;Zhao, Chunyu;Wang, Lu;Xiao, Zhiwei;Rong, Jian;Xia, Xiaotian;Chen, Zhen;Pfister, Stefanie K.;Mast, Natalia;Yutuc, Eylan;Chen, Jiahui;Li, Yinlong;Shao, Tuo;Warnock, Geoffrey, I;Dawoud, Alyaa;Connors, Theresa R.;Oakley, Derek H.;Wei, Huiyi;Wang, Jinghao;Zheng, Zhihua;Xu, Hao;Davenport, April T.;Daunais, James B.;Van, Richard S.;Shao, Yihan;Wang, Yuqin;Zhang, Ming-Rong;Gebhard, Catherine;Pikuleva, Irina;Levey, Allan, I;Griffiths, William J.;Liang, Steven H.
• 通讯作者: Liang, Steven H.