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 然而，有效的治疗方法仍然难以实现。 该领域的共识将注意力集中在从临床开始的早期疾病（临床前 AD） 早在认知症状出现之前，β-淀粉样蛋白 (Aβ) 就在大脑中​​悄然积累。 临床前 AD 现在被认为是有效且持久的 AD 治疗的关键先决条件。 目前评估 Aβ 负荷的可用方法依赖于正电子。 发射断层扫描 (PET) 脑部扫描或脑脊液 (CSF) 分析这些方法价格昂贵， 侵入性、繁琐、不广泛可用且难以扩展。NIA 优先开发新的、 该项目致力于提供安全、灵敏、经济高效、非侵入性的护理点早期 AD 检测技术。 通过加速 FDA 突破性设备指定组合的创新测试来满足这一未满足的需求 药物设备眼部扫描仪（Aftobetin-Sapphire II）可检测晶状体中与 AD 相关的 Aβ。 基于我们在病理确诊的 AD 患者中发现 AD 特异性 Aβ 晶状体病理学，但并非如此 此外，我们还发现与 AD 相关的病理和其他非 AD 神经退行性疾病。 表型在晶状体中的表达早于大脑中的表达，这些发现刺激了蓝宝石的发育。 II 系统镜头 Aβ 扫描仪结合了局部应用的荧光 Aβ 结合示踪配体 (Aftobetin) 和 专门设计的眼部扫描仪，带有集成荧光寿命衰减光谱分析仪，可以可靠地 我们的初步数据显示，以高特异性、灵敏度和信噪比测量晶状体中的 Aβ。 晶状体 Aβ 可将轻度认知障碍 (MCI) 和临床 AD 与正常对照区分开来，且具有可比性 或比淀粉样蛋白 PET 脑部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 的综合检查。 项目建议使用 Sapphire II-Aftobetin 系统添加晶状体 Aβ 测量，以进行早期 AD 检测 在目标 1 中，我们将评估晶状体 Aβ 负荷与 AD 之间的横截面关联。 临床结果，并建立 ATN 生物标志物（Aβ、tau、神经变性；ATN 框架）。 将评估晶状体 Aβ 负荷、AD 临床结果和相同 ATN 之间的纵向关联 生物标志物（如目标 1） 在目标 3 中，我们将进行离体临床病理学相关性比较分析。 BUADRC 参与者死后大脑和晶状体中的 Aβ 负荷和淀粉样蛋白超微结构病理学， 我们预计项目结果将确定晶状体 Aβ 诊断切点。 并加速推出 Sapphire II-Aftobetin 系统，以评估 AD 风险、检测临床前 AD，以及 评估个体患者的早期 AD 和进展。