Rapid saliva test for noninvasive diagnostic screening of MCI and dementia

快速唾液测试用于MCI和痴呆的无创诊断筛查 2020年，超过620万美国人患有痴呆症，全国损失3550亿美元。有一个未满足的需求， 用于轻度认知障碍（MCI）和阿尔茨海默病诊断筛查的标准化、成本效益高的测试 因此，我们需要采取措施，使老年痴呆症（AD）的早期发现和治疗能够减少疾病负担和成本。 该SBIR项目的目标是开发一种快速唾液测试用于诊断MCI和AD。第一阶段显示， 关键创新的可行性：标准化唾液方法，经验证的生物标志物测定，10种候选方法 MCI和AD的生物标志物和用于商业侧流免疫测定（LFA）的新唾液盒。的 拟议的II期研究将在老年人中临床验证MCI和AD生物标志物的诊断生物标志物 并开发出一个原型装置来展示商业产品的可行性。SA 1将入组N=400例男性， 2个研究中心年龄≥50岁的女性：N=200例AD、N=100例MCI和N=100例认知正常对照（CN）。参与者 将根据金标准临床和神经认知评估分配到队列中。队列 将在重要的人口统计学和临床特征上匹配。估计拟定样本量 提供≥80%的统计功效和95%的误差范围。将采集N=550份唾液样本：1份样本 来自所有AD、MCI和70个CN的6个连续样品和来自30个CN的6个连续样品。SA 2将测量10种候选生物标志物 在来自SA 1的N=550个唾液样品中。训练集（N=300）的统计建模将使用统计和 机器学习方法来选择复合生物标志物和基于诊断性能的截止值， MCI和AD。潜在的人口统计学和临床协变量将纳入统计模型。的 将使用临床和人口统计学匹配的验证集验证选定的生物标志物和临界值 （N=100）基于诊断准确性、灵敏度和特异性的目标里程碑。系列样品来自 CN将定义生物标志物浓度和生物变异性的正常范围。SA 3将展示一个 在SA 2中验证的MCI-AD生物标志物的原型LFA装置。预期成果：阶段成果 II研究将严格临床验证用于诊断MCI和AD的新唾液生物标志物。大而 代表性样本量（400例MCI和AD表型和分期、年龄、性别和地理区域的受试者） 将提供具有统计学意义的、可推广的临床数据。标准化的分析前唾液处理和 经分析验证的测定将提供准确和可靠的生物标志物数据。原型设备将显示 商业试验的技术可行性。总体而言，该项目具有广泛影响的高潜力 通过提供一种客观、无创和临床可行的生物标志物， 诊断AD和MCI，并将这一创新转化为标准化、可扩展和具有成本效益的点- 在一般人群中进行常规痴呆筛查的护理（POC）测试。申报产品具有 强大的商业潜力基于经过验证的低风险LFA器械，具有已知和可实现的FDA路径， 有竞争力的专利组合，有限的竞争和致力于临床采用的关键意见领袖。

Project Summary Rapid saliva test for noninvasive diagnostic screening of MCI and dementia In 2020, over 6.2 million Americans had dementia costing the nation $355 billion. There is unmet need for a standardized, cost-effective test for diagnostic screening of Mild cognitive impairment (MCI) and Alzheimer’s disease (AD) to move towards early detection and treatment of dementia to reduce disease burden and costs. The goal of this SBIR project is to develop a rapid saliva test for diagnosis of MCI and AD. Phase I showed feasibility of key innovations: standardized saliva methods, validated biomarker assays, 10 candidate biomarkers of MCI and AD and a new saliva cartridge for commercial Lateral Flow Immunoassay (LFA). The proposed Phase II study will clinically validate a diagnostic biomarker of MCI and AD biomarker in older adults and develop a prototype device to show feasibility of the commercial product. SA1 will enroll N=400 males and females age ≥50 at 2 sites: N=200 AD, N=100 MCI and N=100 cognitively normal controls (CN). Participants will be assigned to the cohorts based on a gold standard clinical and neurocognitive evaluation. The cohorts will be matched on important demographics and clinical characteristics. The proposed sample size is estimated to provide ≥80% statistical power with 95% error margin. N=550 saliva samples will be collected: 1 sample from all AD, MCI and 70 CN and 6 serial samples from 30 CN. SA2 will measure the 10 candidate biomarkers in N=550 saliva samples from SA1. Statistical modeling of Training set (N=300) will utilize both statistical and machine learning methods to select a composite biomarker and a cutoff based on diagnostic performance for MCI and AD. Potential demographic and clinical covariates will be included in the statistical model. The selected biomarker and cutoff will be validated using clinically and demographically matched Validation set (N=100) based on targeted milestones for diagnostic accuracy, sensitivity and specificity. Serial samples from CN will define the normal range of biomarker concentration and biological variability. SA3 will demonstrate a prototype LFA device for the MCI-AD biomarker validated in SA2. Expected Outcomes: Results of the Phase II study will rigorously clinically validate a new saliva biomarker for diagnosis of MCI and AD. Large and representative sample size (400 subjects across MCI and AD phenotype and stage, age, sex and geography) will provide statistically significant, generalizable clinical data. Standardized preanalytical saliva handing and analytically validated assays will provide accurate and reliable biomarker data. Prototype device will show technical feasibility of the commercial test. Overall, this project has a high potential for a wide-ranging impact on clinical AD care by providing an objective, noninvasive and clinically feasible biological biomarker for diagnosis of AD and MCI, and translating this innovation into a standardized, scalable and cost-effective point- of-care (POC) test for routine dementia screening in the general population. The proposed product has a strong commercial potential based on a proven and low risk LFA device with known and achievable FDA path, competitive patent portfolio, limited competition and key opinion leaders committed to clinical adoption.