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.

项目总结

项目成果

Assessment of cholesterol homeostasis in the living human brain.

评估活着的人脑中胆固醇稳态。

• 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.