Utilizing epidemiology, imaging and fluid biomarkers in MOG antibody-associated disease to inform prognosis, pathogenesis and therapeutics - PROJECT SUMMARY/ABSTRACT In the first cycle of this RO1 (2019-2024), summarized in 62 MOGAD publications, we provided foundational knowledge that informed 2023 MOGAD diagnostic criteria and clinical trials. However, fundamental gaps in our knowledge of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remain with limited epidemiology data, lack of prognostic biomarkers, incomplete understanding of pathogenesis and no proven treatments. These gaps in MOGAD have hindered prognostication, clinical trial design and recruitment, and development of novel treatments. The long-term goal is to better diagnose, treat, prognosticate, and understand MOGAD. The objective is to utilize epidemiology data, fluid, and imaging outcome biomarkers to inform prognostication, pathophysiology, and therapeutics. The central hypothesis is that MOGAD has a unique epidemiology, distinctive fluid biomarker profile in attacks and longitudinally with hallmark features on innovative imaging. The rationale is that our findings in MOGAD will inform prognostication, surrogate biomarkers for clinical trials, novel targetable therapeutic pathways, and mechanisms of damage and recovery. The hypothesis will be tested by pursuing three specific aims: 1) To determine MOGAD sero-epidemiololgy using unique population-based registries and use big data from our neuroimmunology lab to determine its age, sex, titer dynamics and seasonal distribution; 2) To evaluate the prognostic value of cytokines, chemokines, injury biomarkers, microglial signals, and MOG-specific humoral markers in attacks and longitudinally; 3) To assess microglial activity and myelin integrity including evidence of remyelination using 11C-ER176 microglia positron emission tomography (PET), 11C-PiB myelin PET, and advanced MRI. The disease registries from the USA and Sweden will be screened for MOG-IgG, big data from the neuroimmunology lab will be analyzed and Mayo Clinic patients will be recruited for serum/CSF analyses and advanced imaging studies. The approach is innovative because: 1) Our unique MOGAD biobank, the largest in the world, includes a population-registry of CSF; 2) Use of MOG epitopes, MOG-IgM, MOG-reactive B cells will offer new insight into MOGAD pathogenesis; 3) 11C-ER176 microglia PET and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) offer novel in vivo measures of microglial activity; 4) 11C-PiB myelin PET and MRI neurite orientation dispersion and density imaging are new ways to detect microstructural injury, neurite integrity and remyelination. The proposed research is significant because: 1) MOGAD is an under-studied distinct demyelinating disease with potential for severe morbidity; 2) Determining which MOGAD patients will have a relapsing course will allow earlier treatment or enrollment in trials and prevent disability; 3) Determining the role of cytokines and microglia in MOGAD may assist prognosis and inform pathogenesis. We expect our findings will improve clinical trials, prognostication and mechanistic insight while identifying novel therapeutic targets.
