Motor Profiles as Novel Biomarker for Alzheimer’s Disease

项目摘要/摘要 已建立的阿尔茨海默病(AD)生物标记物，如用PET测量的淀粉样β蛋白，价格昂贵 而且是侵略性的。经济高效、快速且易于管理的运动测量，如握力和步行 速度，已经显示出比AD的认知症状早几年。相对于单一的衡量标准， 联合动态测量和力量测量可提高AD的预测价值。这表明一种复合体 衡量不同运动领域功能的运动特征评分将具有最佳预测性 权力。已知的早期退化的认知和运动脑区域(例如，海马体和 穹隆)，随后在AD疾病过程中(例如，小脑、(前)运动皮质和皮质脊髓束) 轻度认知障碍(MCI)和阿尔茨海默病(AD)患者运动功能障碍的预测。的目标是 这项K01建议有两个方面：1)通过一系列指导，进一步发展申请人的研究技能 活动，以及2)确定MCI和AD的行为和神经运动特征，目的是发展 稳健有效的风险评分算法。我们的中心假设是运动行为综合评分 和神经运动特征评分将MCI和AD患者与健康对照组区分开来，并 与已建立的AD生物标志物(淀粉样蛋白负荷、海马体体积和APOE e4状态)相关。该项目 有三个具体目标：1)量化MCI和AD的行为和神经运动障碍；2)确定 行为和神经运动复合体得分作为新的AD生物标志物；以及3)复制运动复合体 作为AD生物标记物的分数来自越南时期的双胞胎衰老研究的一个大的独立样本。 培训计划旨在建立对应聘者至关重要的领域的专业知识，以进行 建议开展研究，并成为AD领域的独立调查者。以下是培训目标 已与指导团队密切合作确定：a)建立临床视角和 在MCI和AD方面开展有效研究所需的概念框架；b)在以下方面发展专门知识 与预测建模相关的机器学习；c)深入了解神经运动 MCI和AD的体征和功能；以及d)发展AD生物标志物的专门知识及其在AD中的作用 病因学。培训将由AD的临床专家(Duff博士)和AD领域的领导者密切监督 衰老中的神经运动功能障碍(罗萨诺博士)、AD生物标志物(福斯特博士)、MCI危险因素(克莱门博士)以及 机器学习(塔斯迪岑博士)。候选人的最佳制度环境进一步确保了成功 培训和研究计划将为R01应用程序提供预测MCI到AD的数据 从运动轮廓综合分数过渡。这项拟议的研究做出了重大贡献 致力于开发新的经济高效的AD生物标记物，这些生物标记物可以丰富临床试验和 诊断目的，与国家安全局的使命一致。

PROJECT SUMMARY / ABSTRACT Established biomarkers for Alzheimer's disease (AD), such as amyloid beta measured with PET, are expensive and invasive. Cost-efficient, quick, and easy-to-administer motor measures, such as grip strength and walking speed, have shown to precede the cognitive symptoms of AD by several years. Relative to single measures, combining ambulatory and strength measures boosts predictive value for AD. This suggests that a composite motor profile score that weighs functions spanning the breadth of motor domains will have optimal predictive power. Cognitive and motor brain regions that are known to degenerate early (e.g., the hippocampus and fornix) and later in the AD disease process (e.g., the cerebellum, (pre)motor cortex, and corticospinal tract) are candidates for the prediction of motor dysfunction in mild cognitive impairment (MCI) and AD. The objective of this K01 proposal is two-fold: 1) to further develop the research skills of the applicant with a series of mentored activities, and 2) to identify the behavioral and neural motor profiles of MCI and AD with the aim of developing a robust and valid risk scoring algorithm. Our central hypothesis is that a motor behavioral composite score and neural motor profile score distinguish individuals with MCI and AD from healthy control subjects, and are related to established AD biomarkers (amyloid burden, hippocampal volume, and APOE e4 status). The project has three specific aims: 1) Quantify behavioral and neural motor dysfunction in MCI and AD; 2) Identify behavioral and neural motor composite scores as novel AD biomarkers; and 3) Replicate a motor composite score as AD biomarker in a large independent sample from the Vietnam Era Twin Study of Aging. The training plan aims to establish expertise in areas that are crucial for the candidate to conduct the proposed research and to become an independent investigator in the field of AD. The following training goals have been identified in close collaboration with the mentoring team: a) establishing a clinical perspective and the conceptual framework required to implement effective research in MCI and AD; b) develop expertise in machine learning relevant to prediction modeling; c) gaining an in-depth understanding of neurological motor signs and function in MCI and AD; and d) develop expertise on AD biomarkers and their perceived role in AD etiology. The training will be closely supervised by clinical experts of AD (Dr. Duff), and leaders in the field of neural motor dysfunction in aging (Dr. Rosano), AD biomarkers (Dr. Foster), MCI risk factors (Dr. Kremen), and machine learning (Dr. Tasdizen). The candidate's optimal institutional environment further ensures the success of the training and research plan that will provide data for an R01 application on the prediction of MCI to AD transition from a motor profile composite score. The proposed research makes a significant contribution towards the development of novel cost-efficient AD biomarkers that can serve to enrich clinical trials and for diagnostic purposes, consistent with the mission of the NIA.