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

基本信息

批准号：
10319544
负责人：
SHANNON L RISACHER
金额：
$ 60.01万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319544
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Alzheimer&apos 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 Diagnosis Clinical Trials 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 Lead 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 base 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&apos s disease prophylactic response screening sensory system tau Proteins therapeutic development tool

项目摘要

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

项目摘要在临床前和临床前识别阿尔茨海默病 (AD) 的灵敏、实用和非侵入性方法迫切需要通过确定治疗目标来改善前驱阶段的患者护理和/或生活方式干预对淀粉样蛋白阳性老年人进行抗淀粉样蛋白治疗的前沿临床试验。成人和前驱 AD 患者以及抗 tau 疗法的未来试验有可能带来新的结果因此，迫切需要开发新的治疗方法。敏感且易于获取的生物标志物，可在标记临床之前检测 AD 相关的病理生理学最近的数据表明感觉功能有轻微的损害，包括视觉、嗅觉和听觉，可能与临床相关的认知下降同时发生，甚至先于感觉功能的测量是理想的。筛选生物标志物因其易于使用、非侵入性和低成本而发生了变化。 AD 早期阶段的感觉功能尚未得到全面研究此外，来自多个领域的感觉测量的组合尚未被实现。这些知识差距是一个重要的瓶颈，因为它阻碍了同一参与者的评估。使用感官测量来识别最有可能从假定疗法中受益的个体的领域了解以前被低估的感觉功能障碍如何让我们了解淀粉样蛋白和 tau 蛋白临床前和前驱 AD 的病理学、神经退行性变和大脑连接将提供完整的了解这些早期变化的性质，这对于改善患者护理具有巨大潜力促进 AD 的早期干预我们的中心假设是感觉功能的早期变化。临床前和前驱 AD 表明大脑中存在 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素”旨在：[1] 检验假设 AD 临床前和前驱阶段视觉、嗅觉和听觉测量的变化是由以下因素驱动的脑淀粉样蛋白和 tau 蛋白沉积和/或神经变性 [2] 检验大脑的假设；感觉网络内的连通性与临床前和临床中的多感觉功能测量相关。前驱 AD；[3] 确定感觉生物标志物的组合是否可以提供更好的预测脑淀粉样蛋白和 tau 蛋白沉积、神经变性和连接性变化比单一测量单独用于临床前和前驱 AD；[4] 评估横截面和纵向感觉的能力预测未来认知能力下降、临床转化和脑萎缩率的措施已成功。完成这些目标有可能改变当前早期诊断的概念和方法，这反过来又将支持感官测量的发展，使其成为易于使用且具有成本效益的诊断方法用于 AD 疗法的筛查、诊断、临床试验以及最终治疗的标记物。 2