Lens β-Amyloid Biomarker for Early Detection of Preclinical Alzheimer's Disease in the Framingham Study

Framingham 研究中用于早期检测临床前阿尔茨海默病的晶状体 β-淀粉样蛋白生物标志物

• 批准号: 10214179
• 负责人: LEE E. GOLDSTEIN
• 金额: $ 168.3万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214179
• 关键词: Address; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Attention; Binding; Binding Proteins; Biological Markers; Blood; Blood Vessels; Brain; Brain Pathology; Brain scan; Cause of Death; Cerebrospinal Fluid; Clinical; Clinical Trials; Code; Cohort Studies; Communities; Computer Analysis; Computer Models; Cost of Illness; Crystalline Lens; Data; Data Science; Data Set; Defect; Dementia; Detection; Development; Devices; Disease; Disease Progression; Down Syndrome; Early Diagnosis; Elderly; Epidemiology; Evaluation; Executive Dysfunction; Eye; Failure; Fluorescence Spectroscopy; Framingham Heart Study; Funding; Genes; Genetic Risk; Genotype; Goals; Gold; Health; Impaired cognition; Inflammation; Ligands; Lipids; Longitudinal cohort; Machine Learning; Magnetic Resonance Imaging; Measurement; Measures; Memory; Memory impairment; Metabolic; Methods; National Heart, Lung, and Blood Institute; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neuropsychological Tests; Noise; Participant; Pathogenesis; Pathologic; Pathology; Patient Recruitments; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Point of Care Technology; Positron-Emission Tomography; Predictive Value; Reporting; Research; Research Personnel; Research Priority; Risk Assessment; Risk Factors; Sapphire; Scanning; Secure; Sensitivity and Specificity; Signal Transduction; Specificity; Spectrum Analysis; Symptoms; System; Techniques; Technology; Test Result; Testing; Therapeutic; Thinness; Topical application; Woman; abeta accumulation; age group; amyloid pathology; apolipoprotein E-4; base; beta amyloid pathology; cardiovascular risk factor; cerebral atrophy; cohort; cost; cost efficient; deep learning algorithm; delta-catenin; design; detection platform; disease phenotype; early detection biomarkers; early onset; effective therapy; executive function; genome wide association study; hippocampal atrophy; improved; individual patient; innovation; lens; medical schools; men; middle age; mild cognitive impairment; multi-ethnic; multimodality; neuroimaging marker; non-demented; normal aging; novel; novel strategies; pre-clinical; predictive marker; presenilin-1; research clinical testing; sex; targeted treatment; tau Proteins; tau-1; white matter; β-amyloid burden

Recent research advances have led to detailed understanding of the pathogenesis of Alzheimer's disease (AD) and development of emerging disease-modifying therapies. Yet effective treatment remains elusive. Repeated failure of AD clinical trials has focused attention on preclinical AD that begins with clinically silent accumulation of β-amyloid (Aβ) in the brain and progresses to onset of cognitive symptoms. Early detection of preclinical AD is now recognized as a prerequisite for effective treatment. Aβ is an accepted “gold standard” AD biomarker. 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 identified development of new, safe, sensitive, cost-efficient, point-of-care technology to detect preclinical AD as a high-priority goal. This project addresses this unmet need by accelerating testing of an innovative drug-device combination eye scanner (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 pathology and phenotypes are expressed far earlier in lens than brain in Framingham Eye Study participants. This and related research led to development of the Sapphire II system that combines a topically-applied Aβ-binding fluorescent ligand (Aftobetin) and a purpose-designed eye scanner with integrated fluorescent lifetime decay spectroscopy analyzer. The eye scanner and ligand reliably measure lens Aβ with high specificity, sensitivity, and signal-to-noise ratio. In Phase 2 clinical trials, the Sapphire II system showed high positive and negative predictive values for AD diagnosis and differentiated mild cognitive impairment (MCI) and clinical AD from normal controls with greater sensitivity and specificity than amyloid-PET scans. This project leverages opportunistic timing of NHLBI-funded basic health exams by adding lens Aβ measurements in well- characterized, community-based longitudinal cohorts in the Framingham Heart Study (FHS). Specifically, we will evaluate lens Aβ burden in two older FHS cohorts (Aim 1; Gen 2, multi-ethnic OmniGen 1) and two middle-aged FHS cohorts (Aim 2; Gen 3, multi-ethnic OmniGen 2), each with longitudinal neuropsychological test battery results, concurrent MRI brains scans, and ancillary datasets relevant to cognitive decline and AD. Lens Aβ measurement will be evaluated using stratified analyses for age, sex, ApoE genotype, and AD risk factors (Aim 3) and computational modeling to construct multi-marker predictive profiles for AD (Aim 4). Results will be used to test our project hypothesis that lens Aβ burden will be elevated in middle-aged and older FHS participants who show evidence of cognitive decline (memory deficits, executive dysfunction), AD neuroimaging biomarkers, or clinical AD. Project results are expected to accelerate clinical introduction of lens Aβ burden as an objective measure 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 和新兴疾病缓解疗法的开发。然而有效的治疗仍然难以实现。重复 AD临床试验的失败将注意力集中在从临床无声积累开始的临床前AD 大脑中 β-淀粉样蛋白 (Aβ) 的增多，并发展为认知症状的出现。临床前 AD 的早期检测 现在被认为是有效治疗的先决条件。 Aβ 是公认的 AD 生物标志物“黄金标准”。 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。这些方法昂贵、侵入性、繁琐、无法广泛使用， 并且难以扩展。 NIA 已确定开发新的、安全的、敏感的、具有成本效益的即时护理 将检测临床前 AD 的技术作为高度优先目标。该项目通过加速解决这一未满足的需求 测试创新的药物设备组合眼扫描仪 (Sapphire II)，该扫描仪可检测 AD 相关的 Aβ 镜片。这种新方法是基于我们在 AD 患者中发现的 AD 特异性 Aβ 晶状体病理学。 病理证实的 AD，但不是其他非 AD 神经退行性疾病或正常衰老。此外，我们 发现弗雷明汉眼中与 AD 相关的病理和表型在晶状体中的表达早于大脑中的表达 研究参与者。这项研究和相关研究促成了 Sapphire II 系统的开发，该系统结合了 局部应用的 Aβ 结合荧光配体 (Aftobetin) 和专门设计的眼部扫描仪，集成了 荧光寿命衰减光谱分析仪。眼部扫描仪和配体可靠地测量晶状体 Aβ 高特异性、灵敏度和信噪比。在 2 期临床试验中，Sapphire II 系统显示 AD 诊断和分化型轻度认知障碍 (MCI) 的阳性和阴性预测值较高 正常对照的临床 AD 比淀粉样蛋白 PET 扫描具有更高的敏感性和特异性。这个项目 通过在健康状况良好的情况下添加晶状体 Aβ 测量，利用 NHLBI 资助的基本健康检查的机会主义时机 弗雷明汉心脏研究 (FHS) 中基于社区的纵向队列特征。具体来说，我们将 评估两个老年 FHS 队列（目标 1；Gen 2，多种族 OmniGen 1）和两个中年人的晶状体 Aβ 负担 FHS 队列（Aim 2；Gen 3，多种族 OmniGen 2），每个队列都有纵向神经心理学测试组 结果、并行 MRI 大脑扫描以及与认知衰退和 AD 相关的辅助数据集。镜片Aβ 将使用年龄、性别、ApoE 基因型和 AD 风险因素的分层分析来评估测量结果（目标 3) 和计算建模来构建 AD 的多标记预测概况（目标 4）。结果将被使用 测试我们的项目假设，即中年和老年 FHS 参与者的晶状体 Aβ 负担会升高 表现出认知能力下降的证据（记忆缺陷、执行功能障碍）、AD 神经影像生物标志物、 或临床AD。项目结果预计将加速晶状体 Aβ 负荷作为目标的临床引入 评估 AD 风险、检测临床前 AD 并评估个体患者的早期 AD 和进展的措施。