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

波士顿大学阿尔茨海默病研究中心验证晶状体 β-淀粉样蛋白作为早期检测阿尔茨海默病的新型生物标志物

• 批准号: 10591150
• 负责人: Michael Alosco
• 金额: $ 82.5万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591150
• 关键词: Acceleration; Address; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Attention; Autopsy; Binding; Binding Proteins; Biological Assay; Biological Markers; Blood; Boston; Brain; Brain Pathology; Brain scan; Breakthrough device; Categories; Cause of Death; Cerebrospinal Fluid; Clinical; Cognition; Consensus; Cost of Illness; Couples; Crystalline Lens; Data; Dementia; Detection; Development; Devices; Diagnosis; Diagnostic; Diagnostic Equipment; Disease; Disparity population; Down Syndrome; Drug Combinations; Early Diagnosis; Evaluation; Eye; Fluorescence Spectroscopy; Funding; Heritability; Image; Impaired cognition; Impairment; Individual; Investigation; Language; Life; Ligands; Light; Link; Magnetic Resonance Imaging; Measurement; Measures; Memory; Methods; Monitor; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurologic; Neuropsychological Tests; Noise; Ointments; Ophthalmoscopes; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Point of Care Technology; Positron-Emission Tomography; Predictive Value; ROC Curve; Race; Reporting; Research; Sample Size; Sapphire; Scanning; Sensitivity and Specificity; Signal Transduction; Specificity; Spectrum Analysis; Spinal Puncture; Sum; Symptoms; System; Technology; Testing; Time; Topical application; Tracer; Ultrastructural Pathology; Universities; Validation; abeta accumulation; apolipoprotein E-4; beta amyloid pathology; clinical biomarkers; clinical center; cohort; comparative; cost effective; cost efficient; design; early detection biomarkers; early onset; effective therapy; genome-wide; hippocampal atrophy; in vivo; indexing; individual patient; innovation; lens; mild cognitive impairment; neurofilament; normal aging; novel; novel marker; novel strategies; point of care; polygenic risk score; pre-clinical; rate of change; research clinical testing; risk variant; sex; tau Proteins; tau-1; β-amyloid burden

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.

最近的研究进展使人们对阿尔茨海默病(AD)的发病机制有了详细的了解 以及开发新的和新兴的疾病修正疗法。然而，有效的治疗方法仍然难以捉摸。 该领域的共识将注意力集中在始于临床的早期疾病(临床前AD)上 早在认知症状出现之前，β-淀粉样蛋白(A-β)就在大脑中静默积聚。早期发现 临床前AD现在被认为是有效和持久治疗AD的关键先决条件。β是一种 公认的“黄金标准”AD生物标记物。目前评估β负荷的现有方法依赖于正电子 发射断层扫描(PET)脑扫描或脑脊液(CSF)分析。这些方法都很昂贵， 侵入性的、笨重的、没有广泛使用的、难以扩展的。NIA已优先开发新的、 安全、敏感、经济高效的非侵入性技术，用于护理点早期AD检测。本项目致力于 通过加快FDA指定的创新突破设备组合的测试来满足这一未得到满足的需求 药物设备眼部扫描仪(Aftobetin-Sapphire II)，检测晶状体中与AD相关的Aβ。这种新的方法是 根据我们在经病理证实的AD患者中发现的AD特异性Aβ晶状体病理，但不是 其他非阿尔茨海默病或正常衰老的神经退行性疾病。此外，我们发现AD相关的病理和 表型在晶状体中的表达要比在大脑中早得多。这些发现刺激了蓝宝石的发展 II系统透镜一种β扫描仪，它结合了局部应用的荧光Aβ结合示踪剂配体(Aftobetin)和 一种专门设计的眼睛扫描仪，集成了荧光寿命衰变光谱分析，可靠地 测量晶状体中的β具有高特异性、灵敏度和信噪比。我们的初步数据显示 A-β区分轻度认知障碍和临床AD与正常对照 或者比淀粉样脑部扫描的灵敏度和特异度更高。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都要接受符合NACC标准的全面检查。这 该项目建议增加使用蓝宝石II-Aftobetin系统的镜头Aβ测量，用于早期AD检测 和纵向监测。在目标1中，我们将评估晶状体AβBurden，AD之间的横断面关联 临床结果，并建立atn生物标记物(Aβ，tau，神经变性；atn框架)。在目标2中，我们 将评估晶状体Aβ负荷、AD临床结果和相同的ATN之间的纵向关联 生物标志物(与目标1相同)。在目标3中，我们将进行体外临床病理对照分析。 BUADRC参与者死后脑和晶状体中的β负荷和淀粉样超微病理， 包括那些在生命中扫描的。我们预计项目结果将确定镜头Aβ的诊断切入点 并加快推出蓝宝石II-Aftobetin系统，以评估AD风险，检测临床前AD，以及 评估个别患者的早期阿尔茨海默病和进展。