Impaired Gait in Older Adults: Pathologies of Alzheimer's disease and Related Disorders

摘要 本提案是根据PAR-15-356：流行病学研究的主要机会提交的。 阿尔茨海默病与认知恢复力本研究将探讨的病理关系， AD和与身体传感器步态相关的脑、脑干和脊髓相关疾病 措施然后，我们将构建并验证AD病理学的步态生物标志物。的病理 阿尔茨海默氏病（AD）在明显的认知障碍发作前数年开始。这一建议建立 我们小组和其他人的工作表明，AD病理学可能在AD发生前几年就导致步态受损， 痴呆最近的一次NIH研讨会得出结论，开发一种对AD相对特异的步态生物标志物 病理学可以识别老年人患AD痴呆症的风险，并有助于早期治疗， 痴呆关键的知识差距阻碍了步态生物标志物的构建。首先，常规步态测量 不是AD病理学的特异性。第二，AD和相关疾病的脑病理学的当前指数 仅占步态变化的一小部分，这表明其他脑部病变仍有待进一步研究。 鉴定第三，先前的尸检研究集中在大脑上，因此尚不清楚AD的病理学和 脑干和脊髓中的相关疾病与步态有关。这一建议得到了 令人信服的初步工作。我们发现：1）AD和相关疾病的病理学在 脑干和脊髓，并与老年人的步态有关。2)死后脑MRI指数 微血管组织改变和活化的CNS小胶质细胞与步态有关。3)身体传感器步态指标 比传统的步态速度评估更多的移动性维度， 损伤这项研究利用了记忆和衰老项目（MAP，R 01 AG 17917）的数据和参与者， 一项正在进行的AD临床病理学研究，所有患者在死亡时捐献大脑和脊髓。填补关键 知识差距，我们建议收集和量化年度身体传感器步态指标。对于死者，我们将 量化AD和相关疾病的病理以及脑、脑干和脊髓中的活化小胶质细胞 并提取死后脑MRI指标，以确定老年人步态受损的病理基础 (Aim 1和2）。然后，我们将通过以下方式构建对AD病理学相对特异的身体传感器步态生物标志物： 控制非AD病理和活化的小胶质细胞（目的3）。然后在独立的MAP组中， 参与者，我们将验证步态生物标志物，显示它预测认知能力下降和AD痴呆 (Aim 4）。这种生物标志物有可能促进早期治疗，预防数百万老年人的AD痴呆症。 美国人

ABSTRACT This proposal is submitted in response to PAR-15-356: Major Opportunities for Research in Epidemiology of Alzheimer's Disease and Cognitive Resilience. This study will examine the relation of the pathologies of AD and related disorders in brain, brainstem and spinal cord associated with body sensor gait measures. Then we will construct and validate a gait biomarker for AD pathology. The pathology of Alzheimer's disease (AD) begins years prior to the onset of overt cognitive impairment. This proposal builds on work by our group and others suggesting that AD pathology may cause impaired gait years before AD dementia. A recent NIH workshop concluded that the development of a gait biomarker relatively specific for AD pathology may identify older adults at risk for AD dementia and could facilitate early treatments that prevent dementia. Key knowledge gaps impede the construction of a gait biomarker. First, conventional gait measures are not specific for AD pathology. Second, current indices of brain pathologies of AD and related disorders account for only a small proportion of the variance in gait suggesting that other brain pathologies remain to be identified. Third, prior autopsy studies have focused on the brain, so it is unknown if pathologies of AD and related disorders in brainstem and spinal cord are associated with gait. This proposal is supported by compelling preliminary work. We show that: 1) the pathologies of AD and related disorders accumulate in brainstem and spinal cord and are associated with gait in older adults. 2) Postmortem brain MRI indices of microvascular tissue alterations and activated CNS microglia are related to gait. 3) Body sensor gait metrics which assess more dimensions of mobility than conventional gait speed are related to late-life cognitive impairment. This study leverages data and participants in the Memory and Aging Project (MAP, R01AG17917), an ongoing clinical-pathologic study of AD, all of whom donate brain and spinal cord at death. To fill key knowledge gaps, we propose to collect and quantify annual body sensor gait metrics. In decedents, we will quantify pathologies of AD and related disorders and activated microglia in brain, brainstem and spinal cord and extract indices of postmortem brain MRI to determine the pathologic basis of impaired gait in older adults (Aim 1& 2). Then we will construct a body sensor gait biomarker relatively specific for AD pathology by controlling for non-AD pathologies and activated microglia (Aim 3). Then in an independent group of MAP participants, we will validate the gait biomarker by showing that it predicts cognitive decline and AD dementia (Aim 4). This biomarker has potential to facilitate early treatments that prevent AD dementia in millions of older Americans.