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Longitudinal validation of retinal biomarkers against cerebral imaging in preclinical Alzheimer's disease

针对临床前阿尔茨海默病脑成像的视网膜生物标志物的纵向验证

基本信息

批准号：
10704641
负责人：
Jessica Alber
金额：
$ 201.2万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704641
关键词：
Address Algorithms Alzheimer disease detection Alzheimer disease prevention Alzheimer disease screening Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Atlases Biological Assay Biological Markers Blood Brain Brain imaging Caregivers Cause of Death Central Nervous System Cerebrospinal Fluid Cerebrum Clinical Cognitive Cohort Studies Data Detection Development Diagnosis Disease Disease Progression Early identification Elderly Enrollment Evaluation General Population Goals Human Image Impaired cognition Incidence Inclusion Bodies Individual Infrastructure Inner Plexiform Layer Investigation Knowledge Lasers Magnetic Resonance Imaging Measures Monitor Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Ophthalmology Ophthalmoscopy Optical Coherence Tomography Optometry Outcome Participant Pathologic Pathology Patients Phase Plasma Positron-Emission Tomography Prevention trial Public Health Reference Standards Research Retina Retinal Diseases Risk Risk Assessment Scanning Secondary Prevention Sensitivity and Specificity Site Specialist Standardization Symptoms Techniques Testing Therapeutic United States Validation Visit Visual Visualization Work biomarker development brain magnetic resonance imaging burden of illness candidate validation cerebral amyloidosis clinical application clinical research site cost cost efficient critical period follow-up functional loss ganglion cell imaging biomarker minimally invasive novel observational cohort study ophthalmic examination point of care population based pre-clinical prevent preventive intervention prospective retinal imaging retinal nerve fiber layer risk prediction screening specific biomarkers success targeted biomarker tau Proteins uptake

项目摘要

Project Summary/Abstract Alzheimer’s disease (AD) is a gradually progressive neurodegenerative disorder that results in total cognitive and functional loss. To date, disease-modifying therapeutics and secondary prevention efforts have proven ineffective in combating this public health burden, which impacts over 5.8 million individuals, and is the 6th leading cause of death in the United States. The proposed study addresses the critical need for minimally invasive, cost-efficient, scalable, and accessible AD risk screening biomarkers capable of detecting AD in the earliest pathologic stages (preclinical AD) before clinical symptoms are evident. We target biomarkers in the human retina, a part of the central nervous system (CNS), as they can be visualized non-invasively using standard ophthalmologic techniques and show promise for early AD risk detection and disease monitoring. The Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS) is a longitudinal, observational cohort study to identify sensitive and specific retinal biomarkers of preclinical AD and define their context of use. The objective of the proposed project is to leverage the existing ARIAS infrastructure, adding reference standard brain imaging biomarkers (3T MRI, Ab PET) and novel plasma biomarkers (ptau231, ptau181) to test the central hypothesis that retinal biomarker alterations will predict cerebral biomarker changes and mirror longitudinal cerebral biomarker changes in preclinical AD. Four specific aims will be pursued: (1) identify retinal biomarker differences between preclinical AD participants and cognitively unimpaired (CU) older adults; (2) validate candidate retinal biomarkers cross-sectionally against cerebral biomarkers using Ab PET as a measure of cerebral amyloidosis and MRI as a measure of neurodegeneration; (3) determine the longitudinal relationship between retinal and brain imaging biomarkers, and the ability of baseline retinal biomarkers to predict cognitive and/or brain imaging biomarker changes over 3-year follow-up; and (4) (exploratory) assess the combined sensitivity and specificity of candidate retinal biomarkers with emergent plasma biomarkers in AD risk prediction. Work will be carried out at one existing ARIAS site and two high performing AD research sites. CU participants will complete 5 study visits: screening, baseline, year (Y) 1, Y2, and Y3 follow-up. Brain imaging (MRI and Ab PET) and plasma analysis will occur at baseline and Y3 follow-up. Retinal imaging and cognitive evaluation will occur at baseline and Y1, Y2, and Y3 follow-up. Brain imaging, retinal imaging, cognitive evaluation, and plasma analysis will be supported by four respective cores. Validating retinal biomarkers in preclinical AD is expected to shift focus in AD retinal biomarker development towards systemic, quantitative characterization of retinal risk biomarkers scalable for population-based AD risk screening. Combining plasma biomarkers with sensitive and specific retinal biomarkers could transform AD risk assessment, allowing identification of AD-related changes decades before clinical onset, which may offer the best chance of therapeutic success. Clinical applications include population-based screening for ideal candidates for emerging secondary prevention therapeutics.

项目摘要/摘要阿尔茨海默病(AD)是一种渐进性神经退行性疾病，导致完全认知和功能丧失。到目前为止，疾病修正疗法和二级预防努力已经证明。在抗击这一影响到580多万人的公共卫生负担方面不力，是第六位是美国最大的死因。拟议的研究解决了对最低限度的侵入性、经济高效、可扩展和可访问的AD风险筛查生物标记物能够在临床症状出现前的最早病理阶段(临床前AD)。我们的目标是生物标记物人类视网膜，中枢神经系统(CNS)的一部分，因为它们可以非侵入性地使用标准的眼科技术，并显示出早期AD风险检测和疾病监测的前景。这个阿尔茨海默病研究的视网膜成像图谱(ARIAS)是一项纵向的观察性队列研究，旨在确定临床前阿尔茨海默病的敏感和特异的视网膜生物标志物，并定义它们的使用背景。该计划的目标是拟议的项目是利用现有的Arias基础设施，添加参考标准脑成像用于检验中心假说的生物标志物(3T MRI，AbPET)和新的血浆生物标志物(ptau231，ptau181) 视网膜生物标记物的改变将预测脑生物标记物的变化并反映大脑的纵向临床前阿尔茨海默病的生物标志物变化。将追求四个具体目标：(1)识别视网膜生物标志物的差异临床前AD患者和认知正常(CU)老年人之间的关系；(2)验证候选视网膜脑淀粉样变性的生物标志物与脑生物标志物的横截面对比研究和MRI作为神经退行性变的一种度量；(3)确定视网膜和脑成像生物标记物，以及基线视网膜生物标记物预测认知和/或脑成像的能力生物标记物在3年内的变化；和(4)(探索性)评估联合敏感性和特异性候选视网膜生物标记物与紧急血浆生物标记物在AD风险预测中的作用。将开展工作在一个现有的Arias站点和两个高性能AD研究站点。CU参与者将完成5项研究访问：筛查、基线、第1年、第2年和第3年随访。脑成像(MRI和AbPET)和血浆分析将在基线和Y3年后续进行。视网膜成像和认知评估将在基线时进行 Y1、Y2、Y3随访。脑成像、视网膜成像、认知评估和血浆分析将由四个相应的核心支持。在临床前AD中验证视网膜生物标记物预计将转移重点视网膜生物标记物朝着系统、定量表征视网膜危险生物标记物的方向发展可扩展以进行基于人群的AD风险筛查。将血浆生物标志物与敏感性和特异性结合起来视网膜生物标记物可能改变AD风险评估，使数十年来识别AD相关变化成为可能在临床发作之前，这可能是治疗成功的最好机会。临床应用包括以人群为基础筛选新出现的二级预防疗法的理想候选者。