PROJECT SUMMARY/ABSTRACT Progressive supranuclear palsy (PSP) is a fatal, progressive, incurable neurodegenerative tauopathy. Falls resulting from gait and balance impairments are a cardinal feature of the disease and occur in all PSP syndromes. Currently, detection of these abnormalities relies on largely subjective clinical examination and scales. There are no standardized ways to quantify specific features of gait and balance impairments in PSP. Diagnostic, and prognostic tests focusing on patient relevant outcomes such as gait related disability are needed. Motion analysis technology can be used for objective qualification of gait and balance variables. This offers an opportunity to develop patient-centric diagnostic tools that can measure features of gait impairment and its impact on risk for falls. Laboratory-based video motion capture utilizes multiple high frequency cameras in a well calibrated controlled environment to generate a three-dimensional model of human locomotion and balance. This is considered the most accurate and reliable method of motion analysis. Our project will utilize laboratory-based motion capture to identify gait metrics that best characterize PSP Richardson syndrome, PSP-cortical and PSP-subcortical syndromes and distinguish PSP from normal controls. However, accredited motion analysis labs are not readily accessible, and require an elaborate usually expensive set-up. Body-worn motion-sensing devices offer a feasible alternative. They are cost-effective, portable, easy to use in ambulatory settings. However, it is essential to establish reliability and accuracy of these devices in specific patient populations and assess clinical significance of the data captured. Therefore, in this project we will employ a body-worn motion sensing device or inertial monitoring unit (IMU) to detect gait and balance metrics that best characterize PSP. The data from the IMU will then be compared to the motion analysis lab to establish its accuracy. Gait metrics have the potential to serve as patient-centric outcome measures in PSP. In this project we will also use these variables to analyze neurobiological mechanisms underlying gait and balance impairment in PSP. We will correlate the identified gait and balance metrics with volumetric magnetic resonance imaging (MRI), diffusion MRI (dMRI) and tractography to determine patterns of disruption of cortical and subcortical motor control systems in PSP. The effect of sex as a biologically significant variable will be assessed. Age will be a covariate to identify gait abnormalities that are specifically related to disease state and not secondary to normal aging. The outcomes of this research project will contribute to development of patient centric outcome measures, assessment of clinical heterogeneity and understanding of mechanisms of gait impairment in PSP syndromes. Future directions will include longitudinal assessment and comparative analyses across related neurodegenerative diseases to advance diagnosis and development of patient centric outcome measures for clinical trials.

PROJECT NARRATIVE Gait and balance impairment are an important cause of disability and death in patients with progressive supranuclear palsy, but diagnostic tests and treatments are lacking. We aim to describe objectively quantifiable metrics of gait and balance impairment in progressive supranuclear palsy and determine the underlying mechanism using advanced neuroimaging. Knowledge gained from this work will improve our understanding of progressive supranuclear palsy, identify those who are at risk for falls, and evaluate treatments that could reduce death and disability from falls.