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

常染色体显性阿尔茨海默病视网膜生物标志物的开发：一项试点研究

• 批准号: 10300246
• 负责人: Jessica Alber
• 金额: $ 45.89万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300246
• 关键词: Address; Adult Children; Age; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Area; Biological Assay; Biological Markers; Brain; Cerebral cortex; Cerebrospinal Fluid; Cerebrum; Clinic; Clinical; Control Groups; DNA Sequence Alteration; Data; Deposition; Detection; Development; Disease; Elderly; Evaluation; Foundations; Fundus; General Population; Goals; Gold; Hereditary Disease; Human; Image; Impaired cognition; Inclusion Bodies; Individual; Infrastructure; Inherited; Inner Plexiform Layer; Lasers; Longitudinal Studies; Longitudinal cohort study; Measures; Methods; Morphology; Mutation; Neuraxis; Neurobiology; Neurodegenerative Disorders; Neurons; Ophthalmic examination and evaluation; Ophthalmology; Ophthalmoscopy; Optical Coherence Tomography; Optometry; Outcomes Research; Participant; Pathologic; Pathology; Penetrance; Phase; Pilot Projects; Population; Positron-Emission Tomography; Protocols documentation; Public Health; Research; Research Personnel; Retina; Retinal Diseases; Risk; Risk Assessment; Scanning; Secondary Prevention; Specialist; Standardization; Structure; Surface; Symptoms; Techniques; Testing; Therapeutic; Thick; Validation; Visit; Visual; Work; autosomal dominant Alzheimer' s disease; base; biomarker development; cohort; combat; cost; cost efficient; design; functional loss; ganglion cell; genetic pedigree; macula; medical specialties; mutation carrier; performance site; point of care; population based; pre-clinical; prevent; retinal imaging; retinal nerve fiber layer; routine screening; screening; specific biomarkers; targeted biomarker; β-amyloid burden

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.

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，最终导致了总体 认知和功能损失。迄今为止，调整疾病的疗法和二次预防措施 战斗这一重要的公共卫生伯恩已被证明无效。拟议的项目将解决关键 需要开发非侵入性，成本效益，可扩展性和可访问的广告风险筛查生物标志物， 能够在最早的病理阶段（临床前AD）中检测AD，在临床症状是 证据。我们将针对人类视网膜中的生物标志物，这是中枢神经系统（CNS）的扩展 可以使用标准眼科技术可视化非侵入性。常染色体占主导地位的阿尔茨海默氏症 疾病（ADAD）是AD中视网膜风险生物标志物发展的特别有用人群，因为它允许 在临床症状出现之前数十年的渐近个体的研究。这个目的 研究是为了检查ADAD之间的永久神经元层形态和β-淀粉样蛋白（Aß）差异 突变载体和非载体，并确定残留生物标志物在预测中的效用 AßBurnen处于ADAD最早的病理生理阶段。我们的中心假设是ADAD突变 携带者和非载体将在永久神经元层的形态和 Aß的存在，并且视网膜Aß将预测脑Aß，如Aß极性发射断层扫描所测量 （PET）和/或脑脊液（CSF）测定法。在强大的初步数据的指导下，本研究将追求两个 具体目的：1）确定ADAD突变载体和非携带者之间的视网膜生物标志物差异；和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 目的，我们将利用严格设计的全球队列的基础设施，主要继承了阿尔茨海默氏症 网络 - 观察性（Dian-OBS），具有ADAD突变的参与者和内置对照组一致 突变非载体。黛安·奥布（Dian-Obs 从18岁起的突变，包括AD生物标志物测试（AB PET，CSF）的常规，两年的研究访问， 可以比较残留的生物标志物改变与经过验证的AD风险生物标志物。工作将是 在三个参与的Dian-Obs临床表现站点进行。拟议的工作是第一个 表征ADAD的视网膜生物标志物变化。重要的是，它将为 开发Dian-Obs中的纵向视网膜生物标志物研究，以在受试者的视网膜变化中进行研究 病理学并确定哪些残留生物标志物在AD的每个阶段都具有敏感和特异性 病理生理级联。调查结果具有重要的翻译应用，作为对广告风险的筛查 - 常规眼科检查中的护理临床医生有可能改变AD风险评估并确定理想的人 用于二级预防疗法。