Salivary Extracellular Vesicles as Biomarkers for Alzheimer's Disease and Related Disorders

唾液细胞外囊泡作为阿尔茨海默病和相关疾病的生物标志物

• 批准号: 10620750
• 负责人: Jill Kreiling
• 金额: $ 79.31万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620750
• 关键词: Address; Administrative Supplement; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid deposition; Amyotrophic Lateral Sclerosis; Biological; Biological Assay; Biological Markers; Blood; Blood Tests; Brain; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Custom; Data; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Frontotemporal Dementia; Functional disorder; Goals; Hospitals; Image; Impaired cognition; Individual; Inflammation; Intervention; Investigation; Liquid substance; Measures; Messenger RNA; MicroRNAs; Monitor; Morbidity - disease rate; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; PET positivity; Parkinson Disease; Participant; Pathologic; Pathology; Pathway interactions; Patients; Phase; Phenotype; Population; Positron-Emission Tomography; Predictive Value; Preparation; Prevention; Prevention strategy; Proteins; Proteomics; Publishing; RNA; Research; Research Personnel; Rhode Island; Risk; Risk Factors; Saliva; Salivary; Screening procedure; System; TBI Patients; Testing; Therapeutic Intervention; Transcript; Treatment Effectiveness; Universities; Variant; Vesicle; alpha synuclein; biomarker identification; biomarker panel; cohort; cost; early detection biomarkers; effective therapy; experimental study; extracellular vesicles; high risk; lonely individuals; mild cognitive impairment; mortality; multidisciplinary; neuroinflammation; point of care; potential biomarker; pre-clinical; prevent; protein TDP-43; protein biomarkers; recruit; screening; tau Proteins; therapeutic effectiveness; transcriptomics; trend

Project Summary: Alzheimer's disease (AD) and Related Disorders (ADRD), including frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and amyotrophic lateral sclerosis (ALS), cause significant morbidity and mortality in aging populations. Despite decades of research, there are still no effective treatments to prevent or delay progression of these illnesses. Currently, there are tests available to identify individuals at risk of developing AD, but these tests require either a cerebral spinal fluid assay or positron emission tomography (PET) to measure amyloid levels, which are invasive or cost prohibitive, respectively, limiting their usefulness. While blood based diagnostic tests using amyloid and tau biomarkers are being developed to diagnose AD pathology in symptomatic individuals, their predictive value for preclinical disease is still unknown. Furthermore, there are currently no blood-based tests available for ADRDs. Since AD and ADRD develop over a prolonged period that can span decades, there is a need to identify individuals during this preclinical period when potential interventions may be more effective. To address our inability to diagnose at- risk individuals, we have put together a multidisciplinary team of investigators at Brown University and Rhode Island Hospital with the long-term goal to discover easily accessible biomarkers that can be used in a clinical setting to identify individuals at increased risk of developing AD or ADRD dementias prior to the onset of proteinopathies. Our group recently published that AD-related mRNA transcripts can be detected in extracellular vesicles (EVs) isolated from saliva in patients with traumatic brain injury. Our preliminary data show that patients with mild cognitive impairment (MCI) and mild AD have 43 mRNA transcripts and 5 miRNAs that show altered representation in salivary EVs. In addition, cognitively normal individuals with a PET scan that is positive for amyloid β42 have mRNA and miRNA profiles that are similar to the MCI and mild AD patients. Based on this data we hypothesize that the mRNA, miRNA, and protein composition of salivary EVs will provide valid biomarkers for early diagnosis and following disease progression in patients with AD and related neurodegenerative disorders. To test this hypothesis, we will use transcriptomic and proteomic approaches to define a set of RNA and protein biomarkers present in salivary EVs that predict an individual's risk of developing AD in Specific Aim 1. Specific Aim 2 will extend these investigations to identify RNA and protein biomarkers in salivary EVs isolated from individuals with FTD, PD, DLB, and ALS. In Specific Aim 3 we will determine the dynamics of changes in salivary EV composition during preclinical-to-AD clinical progression by following a cohort of cognitively normal individuals with positive amyloid β42 blood test over a period of 3-5 years. The data obtained in this project will allow us to identify biomarkers present in salivary EVs that can be used as a simple, noninvasive screening mechanism to detect patients at risk of developing AD during the preclinical phase when treatments may be more effective.

项目摘要：阿尔茨海默氏病（AD）和相关疾病（ADRD），包括额颞痴呆 （FTD），帕金森氏病（PD），痴呆症，有路易的身体（DLB）和肌萎缩性侧面硬化症（ALS）， 在衰老人群中引起明显的发病率和死亡率。尽管进行了数十年的研究，但仍然没有 有效的治疗方法可以预防或延迟这些疾病的进展。目前，有测试可用于 识别有开发AD风险的个体，但是这些测试需要大脑脊髓液或正电子 排放断层扫描（PET）以测量淀粉样蛋白水平，分别是侵入性或成本的淀粉样蛋白水平 限制他们的用处。而使用淀粉样蛋白和TAU生物标志物的基于血液的诊断测试正在 开发用于诊断症状个体的AD病理学，其临床前疾病的预测价值是 仍然未知。此外，目前尚无针对ADRD的血液测试。自广告和adrd 在长时间的长时间发展可能跨越数十年的时间里，有必要在此期间识别个人 当潜在干预措施可能更有效的临床前时期。为了解决我们无法诊断的问题 风险个人，我们在布朗大学组成了一个跨学科调查员团队和罗德 岛医院的长期目标是发现易于使用的生物标志物，可用于临床 设置在开始之前识别患有AD或ADRD痴呆症风险增加的人 蛋白质病。我们的小组最近发表了，可以在细胞外检测到与广告相关的mRNA转录本 从唾液中分离出脑损伤患者的蔬菜（EV）。我们的初步数据表明患者 轻度认知障碍（MCI）和轻度AD具有43个mRNA转录本和5个miRNA，显示出改变 唾液电动汽车中的代表。此外，具有PET扫描的认知正常人对 淀粉样蛋白β42具有与MCI和轻度AD患者相似的mRNA和miRNA谱。基于此 数据我们假设唾液电动汽车的mRNA，miRNA和蛋白质组成将提供有效 AD和相关患者的早期诊断和疾病进展的生物标志物 神经退行性疾病。为了检验这一假设，我们将使用转录组和蛋白质组学方法来 定义唾液电动汽车中存在的一组RNA和蛋白质生物标志物 特定目标中的广告。特定目标2将扩展这些投资以识别RNA和蛋白质生物标志物 从具有FTD，PD，DLB和ALS的个体中分离出来的唾液EV中。在特定目标3中，我们将确定 在临床前临床进展过程中唾液EV组成变化的动力学通过遵循 在3 - 5年内，具有淀粉样蛋白β42阳性β42血液测试的认知正常个体的队列。数据 在该项目中获得的将使我们能够识别出唾液电动汽车中存在的生物标志物，可以用作简单的， 无创筛查机制检测在临床前阶段患有AD风险的患者 治疗可能更有效。