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

 描述（由申请人提供）：阐明晚年步态障碍的基础对于预防步态障碍至关重要。最近NIA主办的会议“老龄化、中枢神经系统和运动性”确定了未来工作的目标之一，即量化CNS退行性变化对晚年步态障碍的贡献的研究。特别是，由于之前的CNS完整性研究集中在大脑，脊髓和脑干的退行性变化的贡献是未知的。目前的成像技术不能解决这些地区，由于罕见的尸检标本，从老年死者与详细的步态措施之前，死亡，尸检数据是缺乏的。类似地，尽管对所有运动都至关重要，但对人类步态和姿势起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必要的独特资源，因此该提案可以填补我们知识中的这些空白。我们在小鼠中的临床解剖学研究（R01NS 079623）已经确定了脊髓和脑干中的运动回路，这些回路有助于步态和姿势。令人信服的新数据显示，小鼠和人类的步态控制相似。这些结果证明了使用我们的小鼠研究的数据，以指导选择的定量流动性表型和网站，死后指数将收集在老年人。由NIA资助的一项试点研究（P30AG010161）表明，我们可以在老年人的脊髓和脑干中识别出这些部位，并且这些部位存在退行性变化。这些数据支持这样的假设，即选择脊髓和脑干部位的退行性变化可能与老年人的步态和姿势有关。目前的研究将利用记忆和衰老项目（R01AG17917），该项目将提供临床数据，包括来自全身传感器记录的定量移动表型、死后大脑指数以及脊髓和脑干标本。本申请提出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，该应用具有前所未有的机会，以a）识别脆弱的神经元并确定哪些年龄相关的病理是晚年步态障碍的基础（目标1和2a）和B）哪些脊髓、脑干和脑区域对老年人的步态障碍做出独立贡献（目标2B）。最后，我们将把基于定量运动表型的研究结果转化为传统的步态结构（目标3）。成功地将对大脑CNS贡献的研究扩展到包括脑干和脊髓，在一个大型的具有良好特征的老年人队列中，有可能对我们对晚年步态障碍的理解产生强烈和持续的影响。它将为治疗工作提供新的靶点，以减轻老年步态受损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.