Development of Retinal Biomarkers in Autosomal Dominant Alzheimer's Disease: A pilot study

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种渐进性神经退行性疾病， 认知和功能丧失。迄今为止，改善疾病的治疗和二级预防努力， 事实证明，消除这一重大公共卫生负担是无效的。拟议的项目将解决关键的 需要开发非侵入性的、具有成本效益的、可扩展的和可获得的AD风险筛查生物标志物， 能够在最早的病理阶段（临床前AD）检测AD，在临床症状出现之前， 很明显。我们将靶向人类视网膜中的生物标志物，视网膜是中枢神经系统（CNS）的延伸， 可以使用标准眼科技术非侵入性地可视化。常染色体显性阿尔茨海默 在AD患者中，ADAD是一个特别有用的视网膜风险生物标志物开发人群，因为它允许 对出现临床症状前几十年的无症状个体的研究。的目的 本研究旨在检测ADAD患者和正常人视网膜神经元层形态和β-淀粉样蛋白（A β）的差异， 突变携带者和非携带者，并确定视网膜生物标志物在预测脑 ADAD最早期病理生理阶段中的脂肪负荷。我们的核心假设是ADAD突变 携带者和非携带者将证明视网膜神经元层的形态和视网膜神经元层的结构两者的差异。 存在，并且视网膜Ablation将预测脑Ablation，如通过Ablation正电子发射断层扫描测量 (PET)和/或脑脊液（CSF）测定。在强有力的初步数据的指导下，这项研究将追求两个 具体目的：1）鉴定ADAD突变携带者和非携带者之间的视网膜生物标志物差异;以及2） 确定视网膜生物标志物改变是否预测ADAD中的脑生物标志物状态。完成这些 我们将利用一个严格设计的全球队列的基础设施，显性遗传阿尔茨海默氏症 网络-观察性（DIAN-Obs），与ADAD突变的参与者和内置对照组一致 变异非携带者的数量DIAN-Obs跟踪已知ADAD家系中个体的成年子女 从18岁开始突变，定期进行一年两次的研究访视，包括AD生物标志物检测（Ab PET，CSF）， 允许将视网膜生物标志物改变与经验证的AD风险生物标志物进行比较。工作将 在三个参与DIAN-Obs临床性能研究中心进行。拟议的工作是第一个 表征ADAD中视网膜生物标志物的变化。重要的是，它将为 在DIAN-Obs中开展一项纵向视网膜生物标志物研究，以研究受试者视网膜生物标志物的变化， 病理学，并确定哪些视网膜生物标志物在AD的每个阶段是敏感和特异的 病理生理级联反应这些发现具有重要的转化应用，如通过点- 常规眼科检查的临床医生有可能改变AD风险评估， 用于二级预防治疗。

Project Summary/Abstract Alzheimer’s disease (AD) is a gradually progressive neurodegenerative disorder, ultimately resulting in total cognitive and functional loss. To date, disease-modifying therapeutics and secondary prevention efforts to combat this significant public health burden have proven ineffective. The proposed project will address the critical need for the development of non-invasive, cost-efficient, scalable, and accessible AD risk screening biomarkers, that are capable of detecting AD in the earliest pathologic stages (preclinical AD), before clinical symptoms are evident. We will target biomarkers in the human retina, an extension of the central nervous system (CNS) that can be visualized non-invasively using standard ophthalmologic techniques. Autosomal dominant Alzheimer’s disease (ADAD) is a particularly useful population for retinal risk biomarker development in AD, as it allows for the study of asymptomatic individuals decades prior to the emergence of clinical symptoms. The objective of this study is to examine retinal neuronal layer morphology and beta-amyloid (Aß) differences between ADAD mutation carriers and non-carriers and to determine the utility of retinal biomarkers in the prediction of cerebral Aß burden in the earliest pathophysiologic stages of ADAD. Our central hypothesis is that ADAD mutation carriers and non-carriers will demonstrate differences in both the morphology of retinal neuronal layers and the presence of Aß, and that retinal Aß will predict cerebral Aß as measured by Aß positron emission tomography (PET) and/or cerebrospinal fluid (CSF) assay. Guided by strong preliminary data, this study will pursue two specific aims: 1) identify retinal biomarker differences between ADAD mutation carriers and non-carriers; and 2) determine whether retinal biomarker alterations predict cerebral biomarker status in ADAD. To accomplish these aims, we will leverage the infrastructure of a rigorously-designed global cohort, Dominantly Inherited Alzheimer’s Network – Observational (DIAN-Obs), consistent of participants with ADAD mutations and a built-in control group of mutation non-carriers. DIAN-Obs follows adult children of individuals in a pedigree with a known ADAD mutation from age 18, with regular, bi-annual study visits that include AD biomarker testing (Ab PET, CSF), allowing the comparison of retinal biomarker alterations against validated AD risk biomarkers. Work will be carried out at three participating DIAN-Obs clinical performance sites. The proposed work is the first to characterize retinal biomarker changes in ADAD. Significantly, it will provide foundational data for the development of a longitudinal retinal biomarker study in DIAN-Obs, to study within subjects’ alterations in retinal pathology and determine which retinal biomarkers are sensitive and specific at each stage of the AD pathophysiologic cascade. Findings have important translational applications, as screening for AD risk by point- of-care clinicians at routine eye exams has the potential to transform AD risk assessment and identify those ideal for secondary prevention therapeutics.