Parametric PET of Neuroinflammation for NAFLD-related AD

项目摘要 神经炎症日益被认为是阿尔茨海默病(AD)发病机制中的主要因素 除了β-淀粉样斑块和tau神经原纤维缠结。最近的研究表明，慢性肝脏 非酒精性脂肪性肝病(NAFLD)的炎症可导致神经炎症和AD的迹象。 并能加速AD小鼠的病理征象。由于NAFLD的高患病率，这些 动物模型研究的结果可能会被转化为临床研究，以探索肝脏如何 炎症有助于人类患者的神经炎症并影响AD的发病机制，这可能 为AD的治疗带来新的治疗靶点和策略。然而，要实现这一目标仍然具有挑战性。 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。 在母公司R01的资助下，我们正在开发一种肝脏参数PET方法，使用广泛可用的 放射性示踪剂18F-脱氧葡萄糖(FDG)评估NAFLD患者的肝脏炎症。与标准FDG不同- 主要评估葡萄糖代谢的PET，我们的肝脏参数PET方法利用了动态PET成像 和先进的示踪剂动力学模型，通过量化血液到肝脏的FDG来测量肝脏葡萄糖的转运 运输率。我们对40多例NAFLD患者的临床研究表明，下肝FDG转运是 与较高级别的活检确定的肝脏炎症密切相关，而血糖的测量 新陈代谢并非如此。这些结果表明，肝脏FDG转运是一种潜在的肝脏PET生物标志物 发炎。 这个补充的目标是开发一种类似的基于葡萄糖转运的PET概念来评估 神经炎症对NAFLD相关性AD的评估。我们的中心假设是神经炎症 可能由慢性肝脏炎症触发或加速，并与血糖异常有关 脑内的转运可以用血到脑的FDG转运速率来测量。我们将(1)开发一种 血液到脑FDG转运的PET动力学建模方法和(2)评价血到脑的转运 脑FDG转运率作为NAFLD神经炎症的PET生物标志物。这些因素的综合结果 SPICAL AIMS是对18F-FDG用于评估神经炎症的新能力的概念验证。 由于FDG在AD临床中用于评估神经退行性变(通过测量葡萄糖代谢)， 所提出的方法有可能为阿尔茨海默病提供一种多参数脑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 相同的FDG示踪剂，可以同时评估肝脏和大脑的炎症，以支持新兴的 非酒精性脂肪肝相关不良反应的研究。

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.