Imaging intracerebral and systemic T cell immunity in patients with Alzheimer's disease using 18F-F-AraG

Project Summary (Abstract) Alzheimer disease (AD) is the most prevalent neurodegenerative disorder, with limited treatment options and no curative interventions. While neuroinflammation driven by innate immune cells is a well-established hallmark of AD, the role of adaptive immune responses in the disease remains poorly understood. Accumulating evidence indicates that both intracerebral and peripheral T cells significantly influence the pathophysiology of neurodegeneration in AD, highlighting the need for better understanding of both local and systemic immune processes, particularly in the context of developing successful immunotherapeutic approaches. However, current methods for studying T cell involvement in AD are inadequate for capturing the complex and dynamic nature of immune- neuronal interactions in living patients. The inability of currently used methods to detect local and systemic T cell involvement in living patients with AD represents a major obstacle in our understanding of the role of the adaptive immune responses in AD and development of successful immunotherapy approaches. Positron emission tomography (PET) imaging with T cell-specific agents offers a promising, highly specific, and noninvasive tool for detecting T cell involvement in AD. We propose to investigate [18F]F-AraG, a small molecule PET agent uniquely well- suited for imaging systemic T cell activity, as a biomarker for detecting and quantifying T cell immunity in patients with Alzheimer disease. The immediate goal of this project is the characterization and validation of [18F]F-AraG as an imaging marker of intracerebral and systemic T cell activity in patients with AD. Our long-term goal is to develop highly sensitive and specific noninvasive technique to assess the adaptive immune response and guide development of immunotherapy interventions in patients with AD. The proposed research will deliver a unique and clinic-ready imaging approach to address the critical challenge of detecting intracerebral and peripheral T cell activity in patients living with AD. If proven successful in imaging aberrant T cell activity in patients with AD, [18F]F-AraG PET could revolutionize treatment of Alzheimer’s disease by facilitating the development of novel immunotherapy-based strategies for treating or managing the disease.