Madhusudan Grover

Personal Information
Title Associate Professor
Expertise Gastro-Intestinal (GI)
Institution Mayo Clinic Rochester
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Dynamic Positron Emission Tomography Imaging with 11C-ER176 to Delineate Macrophage Activation in Diabetic Gastroparesis
Diabetic gastroparesis (DG) is a serious complication of diabetes mellitus which results in significant morbidity. Patients suffer from chronic symptoms of nausea, fullness, bloating and abdominal pain. These often result in malnutrition as well as interfere with appropriate management of their diabetes mellitus. Recent advancements driven by work in hyperglycemic animal models as well as full thickness gastric biopsies from patients with DG have demonstrated a macrophage-driven immune dysregulation as central to its pathogenesis. Activated tissue macrophages, likely through paracrine mediators, induce injury to the interstitial cells of Cajal, the gastric pacemaker cells which are also involved in mechanotransduction. An enrichment of markers associated with pro-inflammatory macrophages as well as loss of anti-inflammatory macrophages has been demonstrated in gastroparesis. There are currently no non-invasive ways of assessing immunopathology in the gastric muscle. Additionally, cellular changes can be patchy and untargeted full-thickness biopsies do not allow a comprehensive assessment of the gastric wall. Recently, there have been advancements in radioligands that can be used to delineate activated macrophages. A novel, third-generation translocator protein (TSPO)-specific radioligand is 11C-ER176, which has shown high affinity and excellent in vivo target-to-background binding. Our preliminary data shows that TSPO is expressed in human gastric muscle macrophages. The overall goal of this proposal is to determine the feasibility of 11C-ER176 dynamic PET/CT imaging for detecting macrophage activation in vivo in gastric muscle of patients with DG. In this pilot and feasibility study, we will examine a group of DG patients and matched healthy volunteers with this imaging. Additionally, imaging findings will be validated using tissue assessment of patients using cytometry by time of flight (CyTOF). We anticipate that patients with DG will have enrichment of activated macrophages, which will be detected by an uptake of 11C-ER176 on dynamic PET imaging. This will be associated with enrichment of pro-inflammatory cellular markers on assessment of gastric muscle tissue. Together, this study opens a new paradigm for in vivo assessment of neuromuscular immunopathology in DG, which typically requires invasive, deep tissue biopsy. A successful application of this technique will open avenues for noninvasive assessment and guiding treatment trials for diabetic gastroenteropathy as well as other inflammatory gut disorders.

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