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: 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
• 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' s Disease; Alzheimer' 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

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.

项目概要/摘要 阿尔茨海默病 (AD) 是一种逐渐进行性的神经退行性疾病，会导致总体认知能力丧失 迄今为止，疾病缓解疗法和二级预防工作已得到证明。 无法有效应对这一影响超过 580 万人的公共卫生负担，并且是第六大公共卫生负担 拟议的研究解决了对最低限度死亡的迫切需求。 侵入性、经济高效、可扩展且易于使用的 AD 风险筛查生物标志物，能够检测 AD 我们针对临床症状明显之前的最早病理阶段（临床前 AD）。 人类视网膜是中枢神经系统 (CNS) 的一部分，因为它们可以使用非侵入性方式可视化 标准眼科技术并显示出早期 AD 风险检测和疾病监测的前景。 阿尔茨海默氏症研究视网膜成像图谱 (ARIAS) 是一项纵向观察性队列研究，旨在确定 临床前 AD 的敏感和特异性视网膜生物标志物并定义其使用背景。 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 生物标志物（3T MRI、Ab PET）和新型血浆生物标志物（ptau231、ptau181）来检验中心假设 视网膜生物标志物的改变将预测大脑生物标志物的变化和纵向镜像大脑 临床前 AD 中生物标志物的变化将追求四个具体目标：（1）确定视网膜生物标志物差异。 在临床前 AD 参与者和认知未受损 (CU) 老年人之间进行测试；(2) 验证候选视网膜； 使用 Ab PET 作为脑淀粉样变性的测量方法，对生物标记物与脑生物标记物进行横断面比较 和 MRI 作为神经变性的测量；（3）确定视网膜和 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 3 年随访期间生物标志物的变化；(4)（探索性）评估综合敏感性和特异性 将开展 AD 风险预测中候选视网膜生物标志物与新兴血浆生物标志物的研究。 参与者将在一个现有的 ARIAS 站点和两个高性能 AD 研究站点完成 5 项研究。 就诊：筛查、基线、第 1 年、第 2 年和第 3 年随访脑成像（MRI 和 Ab PET）和血浆。 分析将在基线时进行，第 3 年随访将在基线时进行。 Y1、Y2 和 Y3 随访将进行脑成像、视网膜成像、认知评估和血浆分析。 验证临床前 AD 中的视网膜生物标志物预计将转移焦点。 AD 视网膜生物标志物的开发，旨在系统、定量地表征视网膜风险生物标志物 可扩展用于基于人群的 AD 风险筛查，将血浆生物标志物与敏感且特异性相结合。 视网膜生物标志物可以改变 AD 风险评估，从而能够识别 AD 相关的变化数十年 在临床发作之前，这可能提供治疗成功的最佳机会，包括： 基于人群的筛选，寻找新兴二级预防疗法的理想候选者。

项目成果

Cognitive dysfunction and the 25-item National Eye Institute Visual Function Questionnaire.

认知功能障碍和 25 项国家眼科研究所视觉功能问卷。

• 发表时间: 2022
• 作者: Mozdbar, Sima;Alber, Jessica;Aryal, Subhash;Johnson, Leigh;Moroz, Alina;Rashik, Mohammad;Mostafavi, Amir;O'Bryant, Sid
• 通讯作者: O'Bryant, Sid