Validation of Lens Beta-Amyloid as a Novel Biomarker for Early Detection of Alzheimer's Disease at the Boston University Alzheimer's Disease Research

近年来的研究进展使人们对阿尔茨海默病（AD）的发病机制有了深入的了解 以及开发新的和新兴的疾病修饰疗法。然而，有效的治疗仍然难以捉摸。 该领域的共识将注意力集中在早期疾病（临床前AD）上， β-淀粉样蛋白（A β）在认知症状发作前很久在大脑中无声积累。早期发现 临床前AD现在被认为是有效和持久的AD治疗的关键先决条件。A β是一种 公认的"金标准" AD生物标志物。目前可用的评估A β负荷的方法依赖于正电子 发射断层扫描（PET）脑扫描或脑脊液（CSF）分析。这些方法是昂贵的， 侵入性的、麻烦的、不广泛可用的以及难以扩展的。NIA优先发展新的， 安全、灵敏、成本效益高、无创技术，用于床旁早期AD检测。该项目涉及 通过加速对创新的FDA突破性器械指定组合的测试， 检测透镜中AD相关A β的药物装置眼扫描仪（Aftobetin-Sapphire II）。这种新颖的方法是 基于我们在病理学证实的AD患者中发现AD特异性A β透镜病理学，但 其他非AD神经退行性疾病或正常衰老。此外，我们发现AD相关的病理和 表型在透镜中的表达比在脑中早得多。这些发现刺激了蓝宝石的发展 II系统透镜A β扫描仪，结合局部应用的荧光A β结合示踪配体（Aftobetin）和 专门设计的眼扫描仪，集成荧光寿命衰减光谱分析仪， 以高特异性、灵敏度和信噪比测量透镜中的A β。我们的初步数据显示 透镜A β可区分轻度认知障碍（MCI）和临床AD与正常对照， 或比淀粉样蛋白PET脑扫描更高的灵敏度和特异性。该项目利用纵向临床 核心队列，NIA资助的波士顿大学阿尔茨海默病研究中心（BUADRC; P30AG-072978） BUADRC临床核心队列参与者每年接受符合NACC的全面检查。这 该项目提议使用Sapphire II-Aftobetin系统添加透镜A β测量，用于早期AD检测 纵向监测。在目标1中，我们将评估透镜A β负荷、AD和AD之间的横截面相关性。 临床结局和已建立的ATN生物标志物（A β、tau、神经变性; ATN框架）。在目标2中， 将评价透镜A β负荷、AD临床结局和相同ATN之间的纵向相关性 生物标志物（如目标1）。在目标3中，我们将进行离体的比较临床病理相关性分析， BUADRC参与者死后脑和透镜中的A β负荷和淀粉样蛋白超微结构病理学， 包括在生命中扫描的那些。我们预期项目结果将确定透镜A β诊断临界点 加快引入Sapphire II-Aftobetin系统，以评估AD风险，检测临床前AD， 评估个体患者的早期AD和进展。

Recent research advances have led to detailed understanding of the pathogenesis of Alzheimer’s disease (AD) and development of new and emerging disease-modifying therapies. Yet effective treatment remains elusive. Consensus in the field has focused attention on early-stage disease (preclinical AD) that begins with clinically silent accumulation of β-amyloid (Aβ) in the brain long before onset of cognitive symptoms. Early detection of preclinical AD is now recognized as a critical prerequisite for effective and enduring AD treatment. Aβ is an accepted “gold standard” AD biomarker. Currently available methods to assess Aβ burden rely on positron emission tomography (PET) brain scans or cerebrospinal fluid (CSF) analysis. These methods are expensive, invasive, cumbersome, not widely available, and difficult to scale. The NIA has prioritized development of new, safe, sensitive, cost-efficient, noninvasive technology for point-of-care early AD detection. This project addresses this unmet need by accelerating testing of an innovative FDA Breakthrough Device-designated combination drug-device eye scanner (Aftobetin-Sapphire II) that detects AD-related Aβ in the lens. This novel approach is based on our discovery of AD-specific Aβ lens pathology in patients with pathologically-confirmed AD, but not other non-AD neurodegenerative diseases or normal aging. Moreover, we found that AD-related pathologies and phenotypes are expressed much earlier in lens than brain. These findings spurred development of the Sapphire II system lens Aβ scanner that combines a topically-applied fluorescent Aβ-binding tracer ligand (Aftobetin) and a purpose-designed eye scanner with integrated fluorescent lifetime decay spectroscopy analyzer that reliably measures Aβ in the lens with high specificity, sensitivity, and signal-to-noise ratio. Our preliminary data shows that lens Aβ differentiates mild cognitive impairment (MCI) and clinical AD from normal controls with comparable or greater sensitivity and specificity than amyloid-PET brain scans. This project leverages the longitudinal Clinical Core cohort, NIA-funded Boston University Alzheimer’s Disease Research Center (BUADRC; P30AG-072978) BUADRC Clinical Core cohort participants undergo annual NACC-compliant comprehensive examinations. This project proposes to add lens Aβ measurements using the Sapphire II-Aftobetin system for early AD detection and longitudinal monitoring. In Aim 1, we will evaluate cross-sectional associations between lens Aβ burden, AD clinical outcomes, and established ATN biomarkers (Aβ, tau, neurodegeneration; ATN framework). In Aim 2, we will evaluate longitudinal associations between lens Aβ burden, AD clinical outcomes, and the same ATN biomarkers (as in Aim 1). In Aim 3, we will conduct comparative clinicopathological correlation analysis of ex vivo Aβ burden and amyloid ultrastructural pathology in postmortem brain and lens from BUADRC participants, including those scanned during life. We anticipate that project results will identify lens Aβ diagnostic cut-points and accelerate introduction of the Sapphire II-Aftobetin system to evaluate AD risk, detect preclinical AD, and assess early AD and progression in individual patients.