Reserve against Disability in Early Multiple Sclerosis (RADIEMS) Longitudinal Cohort Study

Multiple sclerosis (MS) is a prevalent chronic neurologic disease diagnosed during early adulthood that often leads to cognitive and sensorimotor decline. Inflammatory demyelinating lesions are key neuropathological features of MS, but neurodegeneration leading to gray matter loss is prominent, begins early, and is the main driver of functional decline. Lack of neuroregenerative therapies or functionally restorative treatments highlights a need to identify modifiable risk and protective factors that preserve gray matter and function. This R01 renewal of the Reserve against Disability in Early MS (RADIEMS) cohort extends our prior work on “reserve” against disability to establish a much-needed framework for investigating functional decline in MS. We propose a dynamic model of reserve in which candidate modifiable risk and protective factors contribute to functional outcomes through (a) maintenance of gray matter (Aim 1), or (b) by modulating one’s ability to maintain function despite loss of gray matter (compensation; Aim 2). RADIEMS enrolled 185 MS patients diagnosed ≤5.0 years (median=2.0) receiving high resolution MRIs and comprehensive cognitive and sensorimotor evaluations at baseline (Y0) and Y3; this renewal adds Y6 and Y8 follow-ups. Retention is excellent (95.0%). Aim 1a investigates whether MIND diet consumption (e.g., leafy greens, fish, nuts, berries) and body mass index (BMI) independently predict maintenance of (a) cerebral gray matter and (b) cognitive and sensorimotor functional outcomes over Y0-Y3-Y6-Y8. We will also evaluate percent body fat measured via bioelectrical impedance as a key culprit in obesity-related morbidity. Aim 1b assesses whether links between MIND diet and BMI with functional outcomes are mediated through gray matter change. Aim 1c analyzes blood and stool samples banked at Y3 for metabolomics & microbiome sequencing to identify nutrient and gut microbiotic mediators of dietary effects on outcomes. Aim 2a: preliminary data link depressed mood to poor cognitive and gait speed / endurance, which fluctuate with mood changes over time. We will assess whether cognitive and sensorimotor functions fluctuate with mood across Y0-Y3-Y6-Y8, and if mood moderates links between gray matter loss and outcomes. We will also investigate independent contributions of positively-valanced aspects of psychological function. Aim 2b assessed whether memory fluctuates with subjective (Y0-Y3-Y6-Y8) and objective (Y6-Y8) sleep disturbance. Little is known about sleep quality and functional outcomes in MS. A large subsample of patients will undergo actigraphy and ambulatory polysomnography at Y6 & Y8; we expect sleep efficiency (especially sleep fragmentation) to explain memory. RADIEMS is a large deeply-phenotyped cohort study of functional outcomes in early MS: a unique and valuable resource for the field. This R01 renewal extends our work on reserve to establish a critical framework for investigating functional decline. This dynamic model will be tested and updated over time to understand mechanistic mediators of risk and protective factors to inform the development of interventions to preserve gray matter and improve functional outcomes.