Parametric PET of Neuroinflammation for NAFLD-related AD

项目总结

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.