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

阿尔茨海默病（AD）和相关疾病（ADRD），包括额颞叶痴呆 (FTD)帕金森病（PD）、路易体痴呆（DLB）和肌萎缩侧索硬化（ALS）， 在老龄人口中引起显著的发病率和死亡率。尽管经过了几十年的研究， 有效的治疗，以防止或延缓这些疾病的进展。目前，有一些测试可用于 识别有发展为AD风险的个体，但这些测试需要脑脊液测定或正电子 发射断层扫描（PET）来测量淀粉样蛋白水平，这分别是侵入性的或成本过高的， 限制了其实用性。虽然使用淀粉样蛋白和tau生物标志物的基于血液的诊断测试正在进行， 开发用于诊断有症状个体的AD病理，其对临床前疾病的预测价值是 仍然未知。此外，目前还没有ADRD的血液检测。由于AD和ADRD 在一个可以跨越几十年的长期发展中，有必要在此期间确定个人 在临床前阶段，潜在的干预措施可能更有效。为了解决我们无法诊断的问题 风险的个人，我们已经在布朗大学和罗德岛州组建了一个多学科的调查小组， Island医院的长期目标是发现可用于临床的易于获得的生物标志物 确定在AD或ADRD痴呆发作前发生AD或ADRD痴呆的风险增加的个体 蛋白质病本课题组最近发表了AD相关的mRNA转录物可以在细胞外 从创伤性脑损伤患者的唾液中分离的囊泡（EV）。我们的初步数据显示， 轻度认知障碍（MCI）和轻度AD患者有43种mRNA转录物和5种miRNA， 在唾液EV中的代表性。此外，PET扫描呈阳性的认知正常个体， 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 我们假设唾液EV的mRNA、miRNA和蛋白质组成将提供有效的 用于AD及相关疾病患者早期诊断和疾病进展后的生物标志物 神经退行性疾病为了验证这一假设，我们将使用转录组学和蛋白质组学方法， 定义一组存在于唾液EV中的RNA和蛋白质生物标志物，这些生物标志物可预测个体发生以下疾病的风险 具体目标1。具体目标2将扩展这些研究，以确定RNA和蛋白质生物标志物 在从FTD、PD、DLB和ALS个体分离的唾液EV中。在具体目标3中，我们将确定 在临床前至AD临床进展期间，通过以下方法观察唾液EV组成变化的动态 在3-5年的时间内具有阳性淀粉样蛋白β42血液测试的认知正常个体的队列。数据 在这个项目中获得的将使我们能够鉴定唾液EV中存在的生物标志物， 无创筛查机制，用于在临床前阶段检测有发生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.