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 疾病改良的疗法的发展仍然难以捉摸。 AD临床试验的失败将其集中在临床前广告上 大脑中的β-淀粉样蛋白（Aβ），并发展为认知症状的发作。 现在被认为是有效治疗的先决条件。 评估Aβ负担的可用方法取决于正电子发射Tomossion断层扫描（PET）脑扫描或 脑脊液（CSF）分析。 NIA的规模差异。 将临床前广告视为高优先级目标的技术。 测试创新的药物磁盘组合眼扫描仪（蓝宝石II），该测试检测到您在您中的AD相关Aβ 这种新颖的方法是基于我们发现的 病理确认的AD，而不是其他不是其他不是神经退行性疾病或正常衰老的 发现与广告相关的病理和表型在镜头上的表达比弗雷明汉眼中的大脑要远。 研究参与者。 局部应用的Aβ结合荧光配体（Awertobetin）和专用设计的眼扫描仪，并集成 荧光寿命衰变光谱分析仪。 高特异性，灵敏度和信噪比。 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） 与淀粉样蛋白-PET扫描相比，具有更高灵敏度和特异性的正常对照中的临床广告。 通过在良好中添加镜头Aβ测量值的NHLBI资助的基本健康考试的杠杆时机 在弗雷明汉心脏研究（FHS）中以社区为基础的纵向人群。 评估两个较旧的FHS队列中的镜头Aβ负担（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MRIINS扫描以及与认知和AD相关的辅助数据集 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的多标记配置文件（AIM 4）。 为了测试我们的项目假设，即中年和老人参与者将增加镜头Aβ负担 谁表现出认知能力下降（记忆缺陷，执行功能障碍），AD神经影像学的证据，生物标志物， 或临床广告结果。 评估AD风险，检测临床前AD并评估早期AD和程序患者。