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.

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 和新兴疾病修饰疗法的发展。然而，有效的治疗仍然难以捉摸。重复 AD临床试验的失败使人们将注意力集中在临床前AD上，这种临床前AD开始于临床无症状的积累 β-淀粉样蛋白（Aβ）在大脑中的表达，并进展为认知症状的发作。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“金标准”AD生物标志物。 评估Aβ负荷的可用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，不是广泛可用的， 并且难以扩展。NIA已经确定了新的、安全的、敏感的、具有成本效益的、即时护理的发展。 检测临床前AD的技术作为一个高度优先的目标。该项目通过加速解决这一未满足的需求， 测试一种创新的药物-设备组合眼部扫描仪（Sapphire II），该扫描仪可检测 透镜。这种新的方法是基于我们发现的AD患者的AD特异性Aβ透镜病理学， 病理学证实的AD，而不是其他非AD神经退行性疾病或正常衰老。而且我们 发现AD相关的病理和表型在斜视眼的透镜中的表达远早于脑 研究参与者。这一点和相关的研究导致了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）和专门设计的眼扫描仪， 荧光寿命衰减光谱分析仪。眼扫描仪和配体可靠地测量透镜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功能障碍（MCI）的阳性和阴性预测值较高 与淀粉样蛋白PET扫描相比，正常对照的临床AD具有更高的灵敏度和特异性。这个项目 利用NHLBI资助的基本健康检查的机会性时机， 特征性的，以社区为基础的纵向队列在心脏研究（FHS）。具体来说，我们将 在两个老年FHS队列（Aim 1; Gen 2，多种族OmniGen 1）和两个中年FHS队列中评价透镜Aβ负荷 FHS队列（Aim 2; Gen 3，多种族OmniGen 2），每个队列均采用纵向神经心理学成套测试 结果、同步MRI脑部扫描以及与认知衰退和AD相关的辅助数据集。透镜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（Aim 3)和计算建模以构建AD的多标记预测谱（Aim 4）。结果将 为了检验我们的项目假设，即透镜Aβ负荷将在中老年FHS参与者中升高 显示认知下降（记忆缺陷，执行功能障碍），AD神经影像学生物标志物， 临床AD预计项目结果将加速将透镜Aβ负荷作为目标的临床引入 评估AD风险，检测临床前AD，评估个体患者的早期AD和进展。