Project Summary/Abstract The purpose of this K23 Mentored Patient-Oriented Research Career Development Award is to develop Kedar Mahajan MD, PhD as an independent translational neuroscience researcher with a focus in multiple sclerosis (MS). This project will allow him to pursue his research plans in understanding neurodegeneration and progressive disability in MS. The structured mentoring plan for clinical, laboratory, and imaging research with semester-long courses in biostatistics and MRI analysis, will provide for an accelerated development of his independent career path. The candidate’s lab mentor, Dr. Bruce Trapp, is a world renowned neuroscience researcher in MS and will oversee his overall development and develop his basic science proficiency. Dr. Daniel Ontaneda’s expertise in the application of advanced MRI techniques to clinical trials, and Dr. Kunio Nakamura’s background in MRI processing and analysis in clinical investigations, will form critical components of the candidate’s mentorship committee. At the Cleveland Clinic Mellen Center, under the supervision of his clinical mentors Daniel Ontaneda MD, MSc and Jeffrey A. Cohen MD, Dr. Mahajan is nearing the completion of a two year clinical and research MS fellowship (National MS Society Clinician Scientist Development Award). He has already collaborated with Dr. Trapp and begun to characterize thalamic demyelination and neurodegeneration and with Dr. Nakamura to correlate thalamic atrophy with extra-thalamic MRI changes. His preliminary data supports the concept that thalamic demyelination is not common in postmortem brains from individuals with MS, and that thalamic atrophy is driven by extra-thalamic injury. Based on these observations, we decided to further examine thalamic pathology and hypothesized that 1) thalamic atrophy will correlate with extra-thalamic injury in the spinal cord and gray matter injury on MRI; 2) thalamic histopathology will show neuronal, axonal, and dendritic injury and loss; 3) atrophy of individual thalamic nuclei will correspond to injury in their respective afferent and efferent projections in cortical regions on MRI, and will correlate with clinical measures associated with their functions. The aims of the proposed research project are: 1) to examine MRI characteristics correlated with thalamic atrophy; 2) investigate pathological correlates of thalami with extremes in atrophy and thalamic lesions; 3) to determine the relationship between individual thalamic nuclear volumes and clinical disability measures. As the MRI sequences in the post-mortem and in vivo projects are similar, correlations between post-mortem MRI metrics to histopathology (Aim 1), and in vivo MRI metrics to quantitative clinical measures (Aim 2), are feasible and particularly meaningful for future clinical studies. The training and development in this structured mentoring plan is designed to provide Dr. Mahajan the framework to seek independent research program funding near the completion of this award, a step towards his goal of becoming a translational physician scientist in MS.

Project Narrative Thalamic atrophy is an early finding in multiple sclerosis (MS) and reflects disease progression and clinical disability. Using an MS rapid post-mortem autopsy program, this proposal will explore thalamic histopathology and MRI characteristics throughout the brain to identify what contributes to this atrophy, and determine which thalamic nuclei may correspond best to clinical measurements to potentially serve as imaging biomarkers of disability. By incorporating training in MRI analysis/physics, biostatistics, diolistic labeling, confocal microscopy, and correlation to quantitative clinical measures, all supervised by an interdisciplinary mentorship committee, the candidate will become adept in the skills necessary to become an independent patient-oriented researcher in the MS field.