PROJECT SUMMARY/ABSTRACT While effective immunotherapies exist for relapsing-remitting multiple sclerosis (RRMS), therapies for progressive MS are limited. In part, this relates to the fact that progressive MS is caused by gradual loss of central nervous system neurons rather than by immune-mediated injury to the myelin around them. However, therapeutic development has also been hampered by the lack of quality outcome measures of clinical disability progression in MS. The inadequacies of the gold standard, the Expanded Disability Status Scale (EDSS), inflate the sample size and length requirements of progressive MS trials. Further, while clinicians may suspect that a person with RRMS has transitioned to a progressive course (secondary progressive MS), it often takes years to confirm using the EDSS. Thus, these patients, perhaps the most informative with much function to lose, are excluded from progressive MS trials. Phase 2 progressive MS trials often rely on whole brain atrophy, measured by brain magnetic resonance imaging (MRI), as the primary outcome, which also has limitations. Considering several neurodegeneration measures concomitantly may improve the efficiency of such trials. Wearable tri-axial actigraphs are non-invasive, inexpensive devices that measure activity patterns in a home- based, real-world setting. Using our sophisticated analytic approach that incorporates multiple dimensions of activity, we are able to distinguish even small numbers of people with MS based on EDSS score. We propose a longitudinal study of 255 MS patients with confirmed, suspected, or no evident progression, tracking EDSS and actigraphy-derived data for up to 4 years. We will obtain baseline and subsequent brain MRIs and other outcomes traditionally used in progressive MS trials to conduct the following aims: Aim 1. To evaluate if actigraphy-derived measures reliably predict subsequent EDSS-confirmed disability progression in established progressive MS patients. Aim 2. To evaluate if actigraphy-derived measures distinguish RRMS patients with and without suspected progression and predict subsequent risk of EDSS-confirmed disability progression. Aim 3. To evaluate the relative contribution of actigraphy-derived measures, when combined with traditional imaging metrics of neurodegeneration, in predicting subsequent clinical disability change. Corresponding directly to the goal of PA-18-145, this project uses cutting-edge, home-based technology to predict MS patient trajectories. We anticipate that actigraphy measures will predict subsequent worsening on EDSS, particularly in those with definite or suspected MS progression, and that adding actigraphy-based measures to imaging measures of neurodegeneration will improve the prediction of subsequent, EDSS- confirmed disability progression. If correct, actigraphy will revolutionize the conduct of therapeutic trials for progressive MS, a critical step for arresting disability accumulation in this common, devastating di...