Parametric PET of Neuroinflammation for NAFLD-related AD

项目摘要 神经炎症越来越被认为是阿尔茨海默病（AD）发病机制的主要参与者 以及β-淀粉样蛋白斑和tau神经元缠结。最近的研究表明， 非酒精性脂肪性肝病（NAFLD）中的炎症可导致神经炎症和野生型AD的体征， 型小鼠并加速AD小鼠的AD病理体征。由于NAFLD的高患病率，这些 动物模型研究的结果可能会转化为临床研究，以探索肝脏 炎症有助于神经炎症并影响人类患者的AD发病机制，这可能 从而为AD治疗提供新的治疗靶点和策略。尽管如此， 这一研究方向的部分原因是缺乏同时评估肝脏炎症的成像工具 和神经炎症。 在父R01赠款下，我们正在开发一种肝脏参数PET方法， 放射性示踪剂18F-氟脱氧葡萄糖（FDG）用于评估NAFLD中的肝脏炎症。与标准FDG不同- PET主要评估葡萄糖代谢，我们的肝脏参数PET方法利用动态PET成像 和先进的示踪动力学建模，通过定量血液到肝脏的FDG来测量肝脏葡萄糖转运 运输率。我们对40多名NAFLD患者的临床研究表明，肝脏FDG转运降低是NAFLD的主要原因。 与较高级别的活检确定的肝脏炎症密切相关，而葡萄糖的措施 新陈代谢没有。这些结果表明，肝脏FDG转运是一个潜在的PET肝脏生物标志物 炎症 该补充的目标是开发一个类似的基于葡萄糖转运的PET概念，用于评估 用于评估NAFLD相关AD的神经炎症。我们的核心假设是神经炎症 可能由慢性肝脏炎症触发或加速，并与异常葡萄糖有关 脑中的FDG转运，其可以使用血液到脑的FDG转运速率来测量。我们将（1）开发一个 PET动力学建模方法用于定量血液-脑FDG转运和（2）评估血液-脑FDG转运。 脑FDG转运率作为NAFLD中神经炎症的PET生物标志物。这些活动的综合成果 具体目的是验证18F-FDG评估神经炎症的新能力的概念验证。 因为FDG被用于AD诊所评估神经变性（通过测量葡萄糖代谢）， 所提出的方法有可能为阿尔茨海默氏症提供多参数脑PET成像解决方案 疾病及相关痴呆（ADRD）。它也可以与我们的肝脏参数PET方法相结合，使用 同样的FDG示踪剂，使肝脑炎症的同时评估，以增强新兴的 NAFLD相关ADRD的研究。

Project Summary Neuroinflammation is increasingly recognized as a major player in the pathogenesis of Alzheimer’s Disease (AD) in addition to beta-amyloid plaques and tau neurofibrillary tangles. Recent studies suggest that chronic liver inflammation in nonalcoholic fatty liver disease (NAFLD) can lead to neuroinflammation and signs of AD in wild- type mice and accelerates pathological signs of AD in AD mice. Due to the high prevalence of NAFLD, these findings from animal-model studies could be potentially translated to clinical research to explore how liver inflammation contributes to neuroinflammation and influences AD pathogenesis in human patients, which may lead to new therapeutic targets and strategies for AD treatment. Nevertheless, it remains challenging to pursue this research direction in part due to the lack of imaging tools for simultaneous assessment of liver inflammation and neuroinflammation. Under the parent R01 grant, we are developing a liver parametric PET method using the widely accessible radiotracer 18F-fluorodeoxyglucose (FDG) to assess liver inflammation in NAFLD. Distinct from standard FDG- PET that mainly assesses glucose metabolism, our liver parametric PET method exploits dynamic PET imaging and advanced tracer kinetic modeling to measure liver glucose transport by quantifying the blood-to-liver FDG transport rate. Our clinical study of over 40 patients with NAFLD showed that lower liver FDG transport was closely associated with higher grades of biopsy-determined liver inflammation, while the measures of glucose metabolism did not. These results demonstrate that liver FDG transport is a potential PET biomarker of liver inflammation. The goal of this supplement is to develop a similar glucose transport-based PET concept for assessing neuroinflammation toward evaluation of NAFLD-related AD. Our central hypothesis is that neuroinflammation may be triggered or accelerated by chronic liver inflammation and is associated with anomalous glucose transport in the brain which can be measured using the blood-to-brain FDG transport rate. We will (1) develop a PET kinetic modeling method for quantification of blood-to-brain FDG transport and (2) evaluate the blood-to- brain FDG transport rate as a PET biomarker of neuroinflammation in NAFLD. The integrated outcome of these specific aims is a proof-of-concept validation of a new ability of 18F-FDG for assessing neuroinflammation. Because FDG is being used in AD clinics for assessing neurodegeneration (by measuring glucose metabolism), the proposed method has the potential to offer a multiparametric brain PET imaging solution for Alzheimer’s disease and related dementias (ADRD). It may also be combined with our liver parametric PET method, using the same FDG tracer, to enable simultaneous evaluation of liver-brain inflammation to empower the emerging research of NAFLD-related ADRD.