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

老年人步态受损：阿尔茨海默病及相关疾病的病理学

• 批准号: 9889016
• 负责人: ARON S BUCHMAN
• 金额: $ 67.75万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889016
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Autopsy; Biological Markers; Brain; Brain Pathology; Brain Stem; Brain region; Cerebrovascular Disorders; Cessation of life; Clinical; Clinical Pathology; Cognition; Cognitive; Data; Dementia; Development; Dimensions; Disease; Early treatment; Educational workshop; Elderly; Epidemiology; Episodic memory; Gait; Gait speed; Histopathology; Immunochemistry; Impaired cognition; Impairment; Knowledge; Lewy Bodies; Magnetic Resonance Imaging; Measures; Memory; Microglia; Modeling; Musculoskeletal Equilibrium; Neurofibrillary Tangles; Participant; Pathologic; Pathology; Pathway interactions; Research; Risk; Spinal; Spinal Cord; Testing; Tissues; United States National Institutes of Health; Work; cognitive development; indexing; mild cognitive impairment; prevent; public health priorities; rate of change; regional difference; resilience; response; specific biomarkers; targeted treatment; wearable sensor technology

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.

抽象的 本提案是为了回应 PAR-15-356：流行病学研究的主要机会 阿尔茨海默病和认知弹性。本研究将探讨病理学之间的关系 AD 以及与身体传感器步态相关的大脑、脑干和脊髓的相关疾病 措施。然后我们将构建并验证 AD 病理学的步态生物标志物。病理学 阿尔茨海默病 (AD) 早在明显的认知障碍发作前数年就开始了。该提案构建 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 失智。最近的 NIH 研讨会得出的结论是，开发一种相对特异的 AD 步态生物标志物 病理学可以识别有 AD 痴呆风险的老年人，并可以促进早期治疗，以预防 失智。关键知识差距阻碍了步态生物标志物的构建。一、常规步态措施 不特定于 AD 病理学。二、当前 AD 及相关疾病的脑病理学指标 仅占步态差异的一小部分，这表明其他脑部病理学仍有待研究 确定。第三，先前的尸检研究主要集中在大脑上，因此尚不清楚 AD 和 AD 的病理学是否与大脑相关。 脑干和脊髓的相关疾病与步态有关。该提案得到以下机构的支持 引人注目的前期工作。我们表明：1）AD 和相关疾病的病理累积在 脑干和脊髓，与老年人的步态有关。 2) 死后脑MRI指标 微血管组织改变和激活的中枢神经系统小胶质细胞与步态有关。 3）身体传感器步态指标 与晚年认知相关的比传统步态速度更多的移动维度 损害。这项研究利用了记忆与衰老项目（MAP，R01AG17917）的数据和参与者， 一项正在进行的 AD 临床病理学研究，所有研究对象在死亡时都捐献了大脑和脊髓。填写密钥 为了弥补知识差距，我们建议收集并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大脑、脑干和脊髓中激活的小胶质细胞 并提取死后脑部 MRI 指数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针对 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 病理和激活的小胶质细胞（目标 3）。然后在一个独立的MAP组中 参与者，我们将通过证明步态生物标志物预测认知能力下降和 AD 痴呆症来验证它 （目标 4）。这种生物标志物有可能促进早期治疗，预防数百万老年人患 AD 痴呆症 美国人。