Multi-Domain Sensory Measures as Biomarkers of Alzheimer's Disease in Preclinical and Prodromal Stages

项目摘要 诊断阿尔茨海默病(AD)的敏感、实用和非侵入性方法 通过确定治疗的靶点，迫切需要前驱阶段来改善患者的护理 和/或生活方式干预。淀粉样蛋白阳性老年患者抗淀粉样蛋白治疗的前沿临床试验 成人和前驱AD患者以及未来抗tau疗法的试验有可能导致新的 临床前阶段针对AD病理生理学的治疗。因此，迫切需要开发新的 在标记临床之前检测AD相关病理生理学的敏感和容易获得的生物标志物 拒绝。最近的数据表明，包括视觉、嗅觉和听力在内的感觉功能存在轻微损害， 可能与临床相关的认知功能下降同时发生，甚至先于临床相关认知功能下降。感觉功能的测量是理想的 筛选生物标志物，因为它们易于使用，非侵入性，和低成本。然而，变化在 阿尔茨海默病非常早期阶段的感觉功能还没有得到全面的研究 神经成像工具。此外，来自多个领域的感觉测量的组合还没有 在相同的参与者中进行评估。这些知识差距是一个重要的瓶颈，因为它阻止了 使用感官测量来确定最有可能从假定的治疗中受益的个人 对于AD。理解以前被低估的感觉功能障碍是如何告诉我们有关淀粉样蛋白和tau的 临床前和先兆AD的病理、神经退行性变和脑连接将提供完整的 了解这些早期变化的性质，这些变化具有通过以下方式改善患者护理的巨大潜力 促进AD的早期干预。我们的中心假设是早期感觉功能的变化 临床前和先兆AD提示大脑中存在与AD相关的神经病理，并反映 阿尔茨海默病相关认知衰退的初期阶段。根据PAR-18-519，该项目的目标是： “感觉和运动变化作为临床前阿尔茨海默病的预测因子”是为了：[1]检验这一假设 阿尔茨海默病临床前和先兆阶段的视觉、嗅觉和听觉测量的变化是由 大脑淀粉样蛋白和tau沉积和/或神经变性；[2]检验改变大脑的假说 感觉网络内的连通性与临床前和临床前的多感觉功能的测量有关 前驱AD；[3]确定感觉生物标记物的组合是否提供了更好的预测 大脑淀粉样蛋白和tau沉积、神经退行性变和连接性改变比单一测量 在临床前和先兆AD中单独存在；[4]评估横断面和纵向感觉能力 预测未来认知、临床转换率和脑萎缩率下降的措施。成功 完成这些目标有可能改变目前早期诊断的概念和方法， 这反过来又将支持感官措施的发展，使其成为可获得和具有成本效益的诊断方法 用于AD治疗的筛查、诊断、临床试验和最终治疗的标记。 2.

PROJECT ABSTRACT Sensitive, practical, and non-invasive methods to identify Alzheimer's disease (AD) in preclinical and prodromal stages are desperately needed to improve patient care by identifying those to target with therapeutic and/or lifestyle interventions. Cutting-edge clinical trials of anti-amyloid therapies in amyloid-positive older adults and prodromal AD patients and future trials of anti-tau therapies have the potential to lead to new treatments targeting AD pathophysiology in preclinical stages. Thus, there is a critical need to develop new sensitive and readily accessible biomarkers to detect AD-related pathophysiology before marked clinical decline. Recent data suggest subtle impairments in sensory function, including vision, olfaction, and hearing, may occur with and even precede clinically relevant cognitive decline. Measures of sensory function are ideal screening biomarkers because of their ease of use, non-invasiveness, and low cost. However, changes in sensory function in very early stages of AD have not been comprehensively investigated with respect to novel neuroimaging tools. Further, the combination of sensory measures from multiple domains has not been evaluated in the same participants. These knowledge gaps are an important bottleneck because it prevents the field from using sensory measures to identify individuals who are most likely to benefit from putative therapies for AD. Understanding how previously underappreciated sensory dysfunction informs us about amyloid and tau pathology, neurodegeneration, and brain connectivity in preclinical and prodromal AD will provide integral knowledge about the nature of these early changes, which has great potential to improve patient care by facilitating early intervention for AD. Our central hypothesis is that early changes in sensory function in preclinical and prodromal AD indicate the presence of AD-related neuropathology in the brain and reflect the initial stages of AD-associated cognitive decline. The aims of this project, in response to PAR-18-519: “Sensory and motor changes as predictors of preclinical Alzheimer's disease,” are to: [1] Test the hypothesis that changes in visual, olfactory, and auditory measures in preclinical and prodromal stages of AD is driven by cerebral amyloid and tau deposition and/or neurodegeneration; [2] Test the hypothesis that altered brain connectivity within sensory networks is associated with measures of multi-sensory function in preclinical and prodromal AD; [3] Determine whether a combination of sensory biomarkers provides a better prediction of cerebral amyloid and tau deposition, neurodegeneration, and changes in connectivity than a single measure alone in preclinical and prodromal AD; [4] Evaluate the ability of cross-sectional and longitudinal sensory measures to predict future decline in cognition, clinical conversion, and brain atrophy rate. Successful completion of these aims has the potential to alter the current concepts and methodologies of early diagnosis, which in turn will support the development of sensory measures as accessible and cost-effective diagnostic markers for use in screening, diagnosis, clinical trials of AD therapies, and ultimately, treatment. 2