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

多域感觉测量作为阿尔茨海默病临床前和前驱阶段的生物标志物

• 批准号: 10614919
• 负责人: SHANNON L RISACHER
• 金额: $ 55.95万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614919
• 关键词: Affect; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid; Atrophic; Auditory; Biological; Biological Markers; Brain; Cerebrum; Clinical; Clinical Research; Clinical Trials; Cognition; Data; Deposition; Deterioration; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Early Diagnosis; Early Intervention; Early treatment; Elderly; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Healthcare; Hearing; Heterogeneity; Impaired cognition; Impairment; Individual; Investigation; Knowledge; Measures; Methodology; Methods; Modality; Motor; Nature; Nerve Degeneration; Participant; Pathology; Patient Care; Patients; Performance; Research Personnel; Rest; Sensory; Smell Perception; Testing; Therapeutic; Therapeutic Intervention; Vision; Visual; cerebral atrophy; clinically relevant; cost; cost effective; diagnostic biomarker; improved; lifestyle intervention; multimodality; multisensory; network dysfunction; neuroimaging; neuroimaging marker; neuropathology; novel; pre-clinical; prevent; prodromal Alzheimer' s disease; prophylactic; response; screening; sensory system; tau Proteins; therapeutic development; tool

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

项目摘要 敏感、实用和非侵入性的方法来识别阿尔茨海默病（AD）， 迫切需要前驱期，以通过确定治疗目标来改善患者护理 和/或生活方式干预。淀粉样蛋白阳性老年人抗淀粉样蛋白治疗的前沿临床试验 成人和前驱AD患者以及未来的抗tau治疗试验有可能导致新的 针对临床前阶段的AD病理生理学的治疗。因此，迫切需要开发新的 敏感且易于获得的生物标志物，以在显著的临床前检测AD相关的病理生理学 下降最近的数据表明，感觉功能，包括视觉，嗅觉和听觉， 可能与临床相关的认知能力下降同时发生，甚至在此之前发生。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， 在AD非常早期阶段的感觉功能还没有关于新的 神经成像工具。此外，来自多个领域的感官测量的组合还没有被实现。 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，因为它阻碍了 从使用感官测量来识别最有可能从假定的治疗中受益的个体 对于AD。了解以前被低估的感觉功能障碍如何告知我们淀粉样蛋白和tau蛋白 临床前和前驱AD中的病理学、神经变性和脑连接将提供 了解这些早期变化的性质，这对改善患者护理有很大的潜力， 促进AD的早期干预。我们的中心假设是， 临床前和前驱AD表明脑中存在AD相关的神经病理学，并反映了 AD相关认知能力下降的初始阶段。该项目的目标是响应PAR-18-519： “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]检验假设 AD临床前和前驱期视觉、嗅觉和听觉指标的变化是由以下因素驱动的： 大脑淀粉样蛋白和tau沉积和/或神经变性; [2]测试改变大脑的假设 感觉网络内的连通性与临床前多感觉功能的测量相关， 前驱AD; [3]确定感觉生物标志物的组合是否提供了更好的预测 大脑淀粉样蛋白和tau蛋白沉积、神经退行性变和连接性变化 在临床前和前驱AD中单独使用; [4]评估横截面和纵向感觉的能力 预测未来认知能力下降、临床转换和脑萎缩率的指标。成功 这些目标的完成具有改变早期诊断的当前概念和方法的潜力， 这反过来又将支持感官测量的发展，作为可获得的和具有成本效益的诊断方法， 用于筛选、诊断、AD治疗的临床试验以及最终治疗的标记物。 2