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

• 批准号: 10524682
• 负责人: Jessica Alber
• 金额: $ 256.64万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 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/10524682
• 关键词: Address; Algorithms; Alzheimer disease detection; Alzheimer disease prevention; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Atlases; Biological Assay; Biological Markers; Blood; Brain; Brain imaging; Caregivers; Cause of Death; 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; Individual; Infrastructure; Inner Plexiform Layer; Investigation; Knowledge; Lasers; Magnetic Resonance Imaging; Measures; Monitor; Nerve Degeneration; Neuraxis; Neurobehavioral Manifestations; Neurodegenerative Disorders; Ophthalmic examination and evaluation; 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; Work; base; biomarker development; 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; 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; Address; Algorithms; Alzheimer disease detection; Alzheimer disease prevention; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Atlases; Biological Assay; Biological Markers; Blood; Brain; Brain imaging; Caregivers; Cause of Death; 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; Individual; Infrastructure; Inner Plexiform Layer; Investigation; Knowledge; Lasers; Magnetic Resonance Imaging; Measures; Monitor; Nerve Degeneration; Neuraxis; Neurobehavioral Manifestations; Neurodegenerative Disorders; Ophthalmic examination and evaluation; 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; Work; base; biomarker development; 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; 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

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 阿尔茨海默氏病（AD）是一种逐渐进行性神经退行性疾病，导致总认知 和功能损失。迄今为止，已经证明了调整疾病的治疗和二级预防工作 无效打击这种公共卫生伯恩（Burnen），影响超过580万人，是第六名 美国的主要死亡原因。拟议的研究解决了最低限度的关键需求 侵入性，成本效益，可扩展性和可访问的广告风险筛查生物标志物，能够检测到AD 证明临床症状之前最早的病理阶段（临床前AD）。我们针对的是生物标志物 人类视网膜是中枢神经系统（CNS）的一部分，因为它们可以非侵入性地可视化 标准眼科技术，并显示出对早期AD风险检测和疾病监测的希望。这 阿尔茨海默氏症研究中的视网膜成像图集（Arias）是一项纵向观察队列研究 临床前AD的敏感和特定的视网膜生物标志物并定义其使用上下文。目的 拟议的项目是利用现有的Arias基础架构，增加参考标准脑成像 生物标志物（3T MRI，AB PET）和新型血浆生物标志物（PTAU231，PTAU181）测试中心假设 视网膜生物标志物的改变将预测脑生物标志物的变化并镜像纵向大脑 临床前广告中的生物标志物变化。将追求四个具体目标：（1）确定残留的生物标志物差异 在临床前广告参与者和认知未受损（CU）的老年人之间； （2）验证候选人残留 生物标志物在横截面上针对脑生物标志物使用AB PET作为脑淀粉样变性的量度 和MRI作为神经变性的量度； （3）确定残留与 脑成像生物标志物以及基线视网膜生物标志物预测认知和/或脑成像的能力 生物标志物在3年的随访中变化； （4）（探索性）评估敏感性和特异性的综合 在AD风险预测中具有新兴血浆生物标志物的候选残留生物标志物工作将进行 在现有的Arias网站和两个高性能的广告研究站点。 CU参与者将完成5项研究 访问：筛查，基线，（Y）1，Y2和Y3随访。脑成像（MRI和AB PET）和等离子体 分析将在基线和Y3随访中进行。视网膜成像和认知评估将在基线时进行 和Y1，Y2和Y3随访。大脑成像，视网膜成像，认知评估和血浆分析将是 由四个相对内核支撑。临床前广告中验证的视网膜生物标志物有望改变重点 AD视网膜生物标志物发展具有视网膜风险生物标志物的系统性，定量表征 可扩展基于人群的广告风险筛查。将血浆生物标志物与敏感和特定 视网膜生物标志物可以改变广告风险评估，从而识别与广告相关的变化数十年 在临床发作之前，这可能会为理论成功提供最佳机会。临床应用包括 基于人群的筛查，以了解新兴次级预防疗法的理想候选者。