Spinal cord and brainstem pathology contributions to late-life gait impairment

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 DESCRIPTION (provided by applicant): Elucidating the basis for late-life gait impairment is essential for its prevention. One of the goals for future work, identified by a recent NIA sponsored conference, Aging, the Central Nervous System, and Mobility, were studies which quantify the contribution of degenerative changes in the CNS to late-life gait impairment. Particularly, since prior studies of CNS integrity have focused on the brain, the contribution of degenerative changes in the spinal cord and brainstem are not known. Current imaging techniques cannot resolve these regions and due to the rarity of post-mortem specimens from older decedents with detailed gait measures prior to death, autopsy data is lacking. Similarly, though vital for all movement, spinal cord and brainstem sites which subserve gait and posture in humans are not known. Over several years, our team has generated unique resources essential so this proposal can fill these gaps in our knowledge. Our clinical-anatomic studies in mice (R01NS079623) have identified motor circuits in spinal cord and brainstem which subserve gait and posture. Compelling new data show similarities in gait control in mice and humans. These results justify using data from our mouse studies to guide the choice of the quantitative mobility phenotypes and sites from which post-mortem indices will be collected in older adults. A pilot study, funded by NIA (P30AG010161), showed that we can identify these sites in spinal cord and brainstems from older adults and degenerative changes are present in these sites. These data support the hypothesis that degenerative changes in select spinal cord and brainstem sites may be associated with gait and posture in old age. The current study will capitalize on the Memory and Aging Project (R01AG17917) which will donate clinical data including quantitative mobility phenotypes derived from whole body sensor recordings, post-mortem brain indices and spinal cord and brainstem specimens. This application proposes to collect novel indices of degenerative changes from spinal cord and brainstem specimens of older individuals. We are unaware of another dataset with similar resources. Thus, this application has an unprecedented opportunity to a) identify vulnerable neurons and determine which age-related pathologies underlie late-life gait impairment (Aim 1 &2a) and b) which spinal cord, brainstem and brain regions make independent contributions to impaired gait in older adults (Aim 2b). Finally, we will translate findings based on quantitative mobility phenotypes to conventional gait constructs (Aim 3). Successfully extending the investigation of CNS contributions from the brain to include the brainstem and spinal cord in a large cohort of well-characterized older adults has potential to make a strong and sustained impact on our understanding of late-life gait impairment. It will provide novel targets for therapeutic efforts t alleviate the growing personal and societal burden of impaired gait in old age.