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.

最近的研究进展导致对阿尔茨海默氏病（AD）发病机理的详细了解 并开发新的和新兴的疾病改良疗法。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临床上开始的早期疾病（临床前AD） 在认知症状发作之前，β-淀粉样蛋白（Aβ）的无声积累。早期检测 临床前广告现在被认为是有效和持久AD治疗的关键先决条件。 Aβ是一个 接受的“黄金标准”广告生物标志物。目前可评估Aβ伯宁的方法依赖于正电子 排放断层扫描（PET）脑扫描或脑脊液（CSF）分析。这些方法很昂贵， 侵入性，繁琐，不可广泛，难以扩展。 NIA优先考虑开发新的 安全，敏感，成本效益，无创的技术，用于护理点的早期广告检测。该项目解决 通过加速创新的FDA突破设备指定组合的测试，这种未满足的需求 药物设备的眼扫描仪（Aftobetin-sapphire II）检测镜片中与AD相关的Aβ。这种新颖的方法是 根据我们在病理确认的AD患者中发现AD特异性Aβ镜头病理学的基础 其他非AD神经退行性疾病或正常衰老。此外，我们发现与广告相关的病理和 表型比大脑更早。这些发现刺激了蓝宝石的发展 II系统晶状体Aβ扫描仪结合了额外应用的荧光Aβ结合示踪剂配体（Aftobetin）和 具有荧光寿命衰变光谱分析仪的专用设计的眼扫描仪，可靠 以高特异性，灵敏度和信噪比的高度测量Aβ。我们的初步数据显示 晶状体Aβ将轻度认知障碍（MCI）和临床AD与正常对照区分开 或比淀粉样-PET脑扫描更高的灵敏度和特异性。该项目利用纵向临床 NIA资助的波士顿大学阿尔茨海默氏病研究中心（BUADRC; P30AG-072978） BUADRC临床核心队列参与者参加年度符合NACC的综合考试。这 使用Sapphire II-屈服系统添加镜片Aβ测量的项目建议，以提早检测 和纵向监测。在AIM 1中，我们将评估镜头AβBurnen，AD之间的横截面关联 临床结果并建立了ATN生物标志物（Aβ，TAU，神经变性； ATN框架）。在AIM 2中，我们 将评估镜头Aβ伯嫩，AD临床结果和相同ATN之间的纵向关联 生物标志物（如AIM 1）。在AIM 3中，我们将对离体进行比较临床病理相关性分析 BUADRC参与者的尸体大脑和镜头中的AβBurnen和淀粉样蛋白超微结构病理学， 包括那些在人生中扫描的人。我们预计项目结果将确定镜头Aβ诊断切点 并加速介绍蓝宝石II-施托丁素系统，以评估AD风险，检测临床前AD和 评估个别患者的早期AD和进展。