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

 描述(由申请人提供)：阐明晚年步态损伤的基础对于预防它是必不可少的。NIA最近主办的一次会议--衰老、中枢神经系统和灵活性--确定了未来工作的目标之一是量化中枢神经系统退行性变化对晚年步态损害的贡献。特别是，由于之前对中枢神经系统完整性的研究主要集中在大脑，脊髓和脑干退行性变化的作用尚不清楚。目前的成像技术无法分辨这些区域，由于较年长死者的尸检标本在死亡前具有详细的步态测量，因此缺乏尸检数据。同样，尽管脊髓和脑干对所有运动都至关重要，但对人类步态和姿势起辅助作用的脊髓和脑干部位尚不清楚。几年来，我们的团队已经产生了独特的资源，因此这项建议可以填补我们知识中的这些空白。我们在小鼠(R01NS079623)上的临床解剖学研究发现，脊髓和脑干中的运动回路对步态和姿势起辅助作用。令人信服的新数据显示，老鼠和人类在步态控制方面有相似之处。这些结果证明，使用我们的小鼠研究数据来指导选择定量的流动性表型和地点，从中收集老年人的死后指数。由NIA(P30AG010161)资助的一项初步研究表明，我们可以从老年人的脊髓和脑中识别出这些部位，这些部位存在退行性变化。这些数据支持这样一种假设，即选定的脊髓和脑干部位的退行性变化可能与老年时的步态和姿势有关。目前的研究将利用记忆和衰老项目(R01AG17917)，该项目将捐赠临床数据，包括来自全身传感器记录的定量活动表型、死后脑指数以及脊髓和脑干标本。这项应用建议从老年人的脊髓和脑干标本中收集退行性变化的新指标。我们不知道另一个具有类似资源的数据集。因此，这一应用程序有一个前所未有的机会来a)识别脆弱的神经元，并确定哪些与年龄相关的病理导致晚年步态损害(目标1和2a)，以及b)脊髓、脑干和大脑区域对老年人步态受损起独立作用(目标2b)。最后，我们将把基于量化活动表型的发现转化为传统的步态结构(目标3)。成功地扩大对大脑中枢神经系统贡献的研究，将脑干和脊髓包括在一大群特征良好的老年人中，可能会对我们对晚年步态障碍的理解产生强大而持久的影响。它将为治疗努力提供新的靶点，以减轻老年步态障碍日益增长的个人和社会负担。

 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.