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

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，最终导致 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 事实证明，与这一重大的公共卫生负担作斗争是无效的。拟议的项目将解决关键的 需要开发非侵入性、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之前，在最早的病理阶段(临床前AD)检测到AD 很明显。我们将瞄准人类视网膜的生物标记物，这是中枢神经系统(CNS)的延伸 可以使用标准眼科技术进行非侵入性可视化。常染色体显性遗传性阿尔茨海默病 疾病(ADAD)是AD中视网膜风险生物标记物开发的一个特别有用的人群，因为它允许 对临床症状出现前几十年无症状个体的研究。这样做的目的是 研究目的是检测ADAD患者视网膜神经元层形态和β-淀粉样蛋白(A？)的差异 突变携带者和非携带者以及视网膜生物标志物在预测脑血管疾病中的作用 在ADAD的最早病理生理阶段的A？负担。我们的中心假设是ADAD突变 携带者和非携带者在视网膜神经元层和视网膜神经元层的形态上存在差异。 A？的存在，视网膜A？将通过A？正电子发射断层扫描来预测大脑A？ (PET)和/或脑脊液(CSF)检测。在强劲的初步数据的指导下，这项研究将继续进行两项 具体目标：1)识别ADAD突变携带者和非携带者之间的视网膜生物标志物差异；2) 确定视网膜生物标志物改变是否预测ADAD患者的脑生物标志物状态。要实现这些目标 AIMS，我们将利用一个严格设计的全球队列的基础设施，多米尼利遗传的阿尔茨海默氏症 网络观察(DIAN-Obs)，具有ADAD突变的参与者和内置对照组的一致性 突变的非携带者。Dian-Obs追踪一个已知ADAD家系中个人的成年子女 从18岁开始突变，每两年定期进行一次研究，包括AD生物标志物检测(抗体PET，脑脊液)， 允许将视网膜生物标记物的变化与经过验证的AD风险生物标记物进行比较。工作将是 在三个参与DIAN-OBS临床表现的地点进行。这项拟议的工作是第一个 描述ADAD中视网膜生物标记物的变化。值得注意的是，它将为 DIAN-OBS纵向视网膜生物标记物研究的进展，以研究受试者视网膜的变化 病理，并确定哪些视网膜生物标志物在AD的每个阶段敏感和特异 病理生理级联反应。这些发现具有重要的翻译应用，如逐点筛查AD风险- 护理临床医生在常规眼科检查中有可能改变AD风险评估并确定那些理想的 用于二级预防疗法。

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.