Obesity as a Driver of Inflammation and Brain Volume Loss in Pediatric Multiple Sclerosis

PROJECT SUMMARY/ABSTRACT Dr. Brenton is a pediatric neurologist whose long-term goal is to become an expert in multiple sclerosis (MS) therapeutics and risk factor modification. The training and mentored research experience proposed will enable him to develop expertise in: 1) the conduct of multi-centered clinical studies, 2) use of MRI as a research tool, and 3) obesity science. Dr. Brenton has assembled an expert team of mentors/advisors to help him. Dr. Karen Johnston (primary mentor) is a highly-successful international expert in clinical trial conduct, Dr. Myla Goldman (co-mentor) is a nationally-recognized expert in MS clinical research, and Dr. Brenda Banwell (co-mentor) is a world-expert in pediatric MS clinical research. Dr. Brenton will take courses pertinent to research methodology, the study of obesity and its relevant biomarkers, and the application of neuroimaging techniques in clinical research. He will also spend 5 weeks at the Children’s Hospital of Philadelphia to gain hands-on experience with Dr. Banwell in the use of neuroimaging as a biomarker for pediatric MS outcomes. Children with MS, the most common autoimmune disease of the central nervous system (CNS), experience failure of age-expected brain growth followed by progressive brain atrophy during adolescence. These children often develop physical and neurocognitive disability at a young age. Childhood obesity is an established risk determinant for pediatric MS, however, the impact of persisting obesity on MS disease course is unknown. In non-MS children and young adults, obesity (a national health epidemic) associates with progressive brain volume loss. In adults with MS, greater levels of obesity are associated with significantly reduced normalized gray matter volumes. This is important, as gray matter atrophy is directly linked with progressive disability in MS. The impact of obesity in children with MS has not been studied and the implications of this are particularly important in a pediatric patient – where the negative impact of obesity on the CNS may exert an even greater detrimental effect on a brain that is still undergoing development. We will conduct a cross-sectional, multi-center cohort study to determine the relationship between obesity and biomarkers of 1) inflammation (measured radiologically by T2-hyperintense inflammatory lesion volumes & serologically by adipocyte-derived cytokines) and 2) neurodegeneration (measured radiologically by whole brain volumetrics & serologically by neurofilament light chain). This study will help define the role of obesity in pediatric MS disease and will set the stage for future intervention studies aimed at modifiable risk factors in MS. Upon completion of this award, Dr. Brenton will be one of the only child neurologists in the world with formal training in pediatric MS in combination with training in obesity science and MS neuroimaging. His proposal represents the first and only prospective study evaluating the role of obesity on pediatric MS disease severity at presentation. This K23 will provide the necessary data and experience to inform future studies, and he will be well-poised to apply for future R01 funding as an independent, collaborative clinician-scientist.