PROJECT SUMMARY Falls are a common public health concern among persons with Multiple Sclerosis (MS), and can substantially decrease quality of life. Current fall detection measures in MS rely upon forward walking speed and balance; however, these measures exhibit limited predictive accuracy for falls. Backward walking (BW) velocity is a promising clinical measure with known relationships to fall history in the elderly and persons with MS. Retrospective reporting of fall is subject to inaccuracy, given the high prevalence of cognitive dysfunction in MS; yet, the predictive accuracy of BW for prospective fall risk remains unknown. There are many factors that may contribute to fall risk, but prior studies have failed to examine mechanisms that may drive the relationship of BW to fall risk. Identification of a clinical marker of fall risk that is related to both underlying neuropathology (i.e., myelin degradation) of key motor white matter tracts and cognitive function is critically needed. Without such a measure, fall rates for MS and targeted rehabilitation for fall prevention is not likely to be realized. The specific aims of this proposal are to 1) Establish the reliability and minimal detectible change for BW as an outcome tool and determine the predictive capacity of BW measures for fall risk over 6 months; 2) Examine the unique contributions of cognitive domains to BW performance; and 3) Determine the contribution of myelin degradation in key tracts to BW performance. Our central hypothesis is that BW velocity is a reliable and valid predictor of future falls that is related to underlying myelin degradation and cognitive dysfunction. The proposed project will use innovative techniques to measure myelin content using myelin water imaging, advanced technologies and approaches for quantifying both laboratory and clinical assessments of walking and cognition and prospective fall monitoring using wearable sensors and survey measurement. Identifying a clinical marker of fall risk that is supported by underlying pathology and cognitive dysfunction addresses a major gap of prior research and has the potential of improving targeted rehabilitation therapies for fall prevention, clinical outcomes and quality of life for persons with MS.