PROJECT SUMMARY/ABSTRACT
Attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can render a patient blind,
paralyzed or comatose and distinguishing it from other demyelinating diseases such as multiple sclerosis (MS)
and aquaporin-4(AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD) is crucial given the
major differences in clinical course, treatment and prognosis. Major knowledge gaps in MOGAD are hindering
patient care and a barrier to understanding its pathogenesis. The absence of MOGAD incidence and
prevalence data and limited knowledge on its epidemiology worldwide directly impacts decisions on when to
order MOG-IgG, healthcare planning, clinical trial design and identification of risk factors. The lack of
prospective USA data regarding the prognostic value of MOG-IgG titer and persistence impacts treatment
decisions. MOG-IgG in cerebrospinal fluid (CSF) is used by clinicians to diagnose MOGAD, yet data on its
diagnostic utility is limited compared to the established utility of serum MOG-IgG. The limited data on MRI
evolution and immuno-pathology hinders our understanding of MOGAD pathogenesis. The long-term goal is to
better diagnose, treat, and understand MOGAD. The objective of this proposal is to determine the incidence
and prevalence of MOGAD, the prognostic value of MOG-IgG testing, the diagnostic utility of CSF MOG-IgG,
the evolution of MRI lesions and the immunopathology. The central hypotheses (supported by the applicants
preliminary data) is that MOGAD epidemiology is similar to AQP4-IgG in the USA but varies by region, that
serum MOG-IgG persistence and high titer predict relapse, that CSF MOG-IgG lacks diagnostic utility, that
MOGAD MRI lesions resolve more often than MS and that immuno-pathological characteristics of MOGAD can
be defined. The rationale is that these findings will directly impact patient care, facilitate clinical trial readiness,
enhance understanding of pathogenesis, and lead to development of novel treatments. The hypothesis will be
tested by pursuing three specific aims: 1) To determine the population-based incidence, prevalence and
frequency of MOGAD versus AQP4-IgG and MS across multiple world regions; 2) To identify the prognostic
value of MOG-IgG titer and persistence, assess the utility of CSF MOG-IgG and compare MRI evolution to MS
and AQP4-IgG NMOSD; 3) To define the immuno-pathology of MOGAD and compare it to MS and AQP4-IgG
NMOSD. To do this we will utilize the largest clinical, sero-epidemiologic and pathologic biobank of
demyelinating disease in the world. The approach is innovative because it uses a novel live-cell flow cytometry
based MOG-IgG assay developed by the team of applicants. The proposed research is significant because it is
expected to guide resource allocation, directly impact patient care by providing guidance on diagnostics and
therapeutics and give insight into pathogenesis. Ultimately, the knowledge of immunopathology may lead to
the development of novel treatments similar to how complement deposition in AQP4-IgG NMOSD pathology
led to phase 2 and 3 trials showing efficacy and safety of eculizumab (a complement inhibitor).