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

摘要 本提案是为响应PAR-15-356：中国流行病学研究的重大机遇而提出的 阿尔茨海默病与认知韧性。这项研究将探讨慢性阻塞性肺疾病的病理关系。 与身体感觉步态相关的脑、脑干和脊髓的AD及相关疾病 措施。然后，我们将构建并验证AD病理的步态生物标志物。的病理学 阿尔茨海默病(AD)在明显的认知损害发生前几年就开始了。这项建议建立了 我们小组和其他人的工作表明，阿尔茨海默病的病理可能会在AD发生前几年导致步态受损 痴呆症。美国国立卫生研究院最近的一次研讨会得出结论，步态生物标记物的开发对AD具有相对特异性 病理学可以确定老年人有患阿尔茨海默病的风险，并可以促进早期治疗，防止 痴呆症。关键的知识差距阻碍了步态生物标记物的构建。首先，传统的步态测量 并不是AD病理所特有的。第二，阿尔茨海默病及相关疾病的脑部病理指标 只占步态变化的一小部分，这表明其他大脑病变仍然存在 已确认身份。第三，以前的尸检研究集中在大脑上，所以尚不清楚AD和AD的病理 脑干和脊髓的相关疾病与步态有关。这项建议得到以下方面的支持 令人信服的前期工作。我们发现：1)阿尔茨海默病和相关疾病的病理在 脑干和脊髓，并与老年人的步态有关。2)死后脑MRI指标 微血管组织改变和中枢神经系统小胶质细胞激活与步态有关。3)身体传感器步态测量 与传统步态速度相比，评估移动性的更多维度与晚年认知有关 减损。这项研究利用了记忆和老龄化项目(MAP，R01AG17917)的数据和参与者， 一项正在进行的阿尔茨海默病的临床病理研究，所有人死后都会捐献大脑和脊髓。填充关键点 针对知识差距，我们建议收集和量化年度身体传感器步态指标。在继承人中，我们将 量化阿尔茨海默病及相关疾病的病理和脑、脑干、脊髓小胶质细胞的激活 并提取死后脑MRI指标以确定老年人步态受损的病理基础 (目标1和2)。然后，我们将构建一个相对特异的AD病理的身体感知步态生物标记物 控制非AD病理和激活的小胶质细胞(目标3)。然后在一组独立的地图中 参与者，我们将通过显示步态生物标记物预测认知能力下降和AD痴呆来验证步态生物标记物 (目标4)。这种生物标志物有可能促进预防数百万老年人阿尔茨海默病的早期治疗 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.