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

项目摘要：阿尔茨海默病(AD)和相关疾病(ADRD)，包括额颞部痴呆 (FTD)、帕金森氏病(PD)、路易体痴呆(DLB)和肌萎缩侧索硬化症(ALS)， 在老龄化人口中造成严重的发病率和死亡率。尽管进行了几十年的研究，但仍然没有 预防或延缓这些疾病进展的有效治疗。目前，有一些测试可用于 确定有患阿尔茨海默病风险的人，但这些测试需要脑脊液分析或正电子 发射断层扫描(PET)测量淀粉样蛋白水平，分别是侵入性的或成本过高的， 限制了它们的用处。虽然使用淀粉样蛋白和tau生物标记物的血液诊断测试正在进行 开发用于诊断有症状的个体的AD病理，它们对临床前疾病的预测价值是 仍然未知。此外，目前还没有基于血液的ADRDS检测方法。自AD和ADRD以来 在长时间的发展，可能跨越几十年，有必要在此期间识别个人 潜在干预措施可能更有效的临床前阶段。为了解决我们无法在- 风险个人，我们已经在布朗大学和罗德组建了一个多学科的调查团队 岛屿医院的长期目标是发现可用于临床的易于获得的生物标记物 在发病前确定罹患AD或ADRD痴呆风险增加的个人 蛋白质病。我们的团队最近发表了一篇文章，称在细胞外可以检测到AD相关的mRNA转录产物 从创伤性脑损伤患者的唾液中分离出小泡(EVS)。我们的初步数据显示，患者 轻度认知障碍(MCI)和轻度AD患者有43个mRNA转录本和5个miRNAs显示改变 在唾液电动汽车中的表达。此外，PET扫描呈阳性的认知正常个体 淀粉样蛋白β42具有类似于轻度认知障碍和轻度阿尔茨海默病患者的基因和miRNA图谱。在此基础上 我们假设唾液EV的mrna、mirna和蛋白质组成将提供有效的 阿尔茨海默病及相关疾病早期诊断和病情进展的生物标志物 神经退行性疾病。为了验证这一假设，我们将使用转录和蛋白质组学方法 定义唾液EV中存在的一组RNA和蛋白质生物标记物，这些生物标记物可以预测个人患上EV的风险 AD在特定目标1.特定目标2将扩大这些研究以识别RNA和蛋白质生物标志物 从FTD、PD、DLB和ALS患者的唾液中分离出EV。在具体目标3中，我们将确定 临床前-AD临床进展过程中唾液EV成分的动态变化 在3-5年的时间里，对认知正常的人进行了淀粉样蛋白β42血液检测阳性的队列。数据 在这个项目中获得的将使我们能够识别唾液电动汽车中存在的生物标志物，这些生物标志物可以作为一种简单的， 非侵入性筛查机制，用于在临床前阶段检测有患AD风险的患者 治疗可能更有效。

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.