PET imaging for neuroimmune function in Alzheimer's disease

项目总结。预期寿命的延长大大增加了老年痴呆症（AD）的发病率。

Project Summary. Increases in life expectancy have greatly increased the frequency of Alzheimer’s disease (AD) and the economic burden on society the disease entails. At present, 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 neuroimmune function disruption occurs early in the AD pathophysiology. Herein we propose the use of a novel imaging strategy for monitoring innate immune function, neuroinflammation, and novel AD treatment response in AD therapy. The strategy involves the use of a specific positron emission tomography (PET) tracer [18F]PF-974 targeting cAMP-dependent cyclic phosphodiesterase subtype 4B (PDE4B). Because cAMP is a critical regulator of microglia homeostasis, while other PDE4 isoforms are often associated with debilitating adverse effects, PDE4B, as the predominant negative modulator for cAMP signaling, represents a promising surrogate biomarker for neuroimmune function and neuroinflammation. PDE4B expression and activity is regulated by inflammation in the brain, and in turn, PDE4B changes reflect altered neuroimmune function. [18F]PF-974 is the only validated PDE4B PET tracer with excellent binding affinity and high selectivity towards PDE4B over other PDE4 isoforms as well as any other major CNS targets. PET imaging evaluation of [18F]PF-974 confirmed high specific binding in the brain of nonhuman primates, which was recently translated to human. The PI and his team are the first group to evaluate brain kinetic and specific binding of [18F]PF- 974 in naïve and neuroinflammation mouse models. Our preliminary studies have shown that the tracer can detect neuroinflammation in LPS-induced (acute and subchronic) neuroinflammation mouse models, which was well- correlated with our immunohistological and pathological findings. To date, there is no direct non-invasive measurement of the distribution and expression of PDE4B in various AD disease, representing a substantial knowledge gap and opportunity to study innate immune function by [18F]PF-974-PET. Therefore, as our specific objectives, utilizing non-invasive [18F]PF-974-PET, we propose to directly monitor PDE4B changes in the brain as an index of neuroinflammation in AD, and evaluate treatment response for novel CSF1R-targeted AD therapies, followed by biological validation. Following this, our long-term goal is to assess the utility of [18F]PF-974-PET as a translational biomarker to provide new information of neuroimmune function in AD pathophysiology and to evaluate treatment response in clinical trials of novel AD drugs.