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.

最近的研究进展已导致对阿尔茨海默氏病（AD）发病机理的详细了解 以及新兴疾病改良疗法的发展。然而有效的治疗仍然难以捉摸。重复 AD临床试验的失败已将注意力集中在临床前AD上，临床前AD始于临床沉默的积累 大脑中的β-淀粉样蛋白（Aβ）的发作，并发展为认知症状的发作。临床前广告的早期检测 现在被认为是有效治疗的先决条件。 Aβ是公认的“黄金标准” AD生物标志物。 可用的评估Aβ伯宁的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，笨重的，不可广泛的， 并且难以扩展。 NIA已经确定了新，安全，敏感，成本效益，护理点的发展 将临床前广告视为高优先级目标的技术。该项目通过加速解决了这种未满足的需求 测试创新的药物磁盘组合眼扫描仪（蓝宝石II），该扫描仪检测到与AD相关的Aβ的测试 镜片。这种新颖的方法是基于我们在患有AD特异性Aβ镜头病理学的患者中发现 病理确认的AD，但没有其他非AD神经退行性疾病或正常衰老。而且，我们 发现与广告相关的病理和表型在镜头上比弗雷明汉眼中的大脑更早。 研究参与者。这项和相关的研究导致了蓝宝石II系统的发展，该系统结合了 局部应用的Aβ结合荧光配体（Aftobetin）和专用设计的眼扫描仪，并具有集成 荧光寿命衰减光谱分析仪。眼睛扫描仪和配体可靠地测量镜头Aβ 高特异性，灵敏度和信噪比。在第2阶段临床试验中，蓝宝石II系统显示 AD诊断和分化的轻度认知障碍（MCI）的高积极和阴性预测值（MCI） 与淀粉样-PET扫描相比，来自正常对照的临床广告具有更大的灵敏度和特异性。这个项目 利用NHLBI资助的基本健康检查的机会时间，通过添加透镜Aβ测量 在弗雷明汉心脏研究（FHS）中以社区为基础的纵向人群。具体来说，我们会的 评估两个较旧的FHS队列中的镜头AβBurnen（AIM 1; Gen 2，多种族综合1）和两个中年 FHS队列（AIM 2; Gen 3，多种族无水2），每个人都有纵向神经心理学测试电池 结果，同时进行的MRI大脑扫描以及与认知下降和AD相关的辅助数据集。镜头Aβ 将使用分层分析对年龄，性别，APOE基因型和AD风险因素进行评估（AIM 3）和计算建模以构建AD的多标记预测概况（AIM 4）。结果将被使用 为了测试我们的项目假设，即中年和较旧的FHS参与者将升高镜头Aβ燃烧 谁显示了认知能力下降的证据（记忆定义，执行功能障碍），AD神经影像学，生物标志物， 或临床广告。预计项目结果将加速临床引入镜头AβBurnen作为目标 评估AD风险，检测临床前AD并评估个别患者的早期AD和进展的措施。