Extraceullar Vesicle Biomarkers for Prediction of Cognitive Decline, Ab and TAU Accumulation, and atrophy in Preclinical Alzheimer's Disease

在以前的研究中，我们的部分开创了一种捕获富集神经元来源（通过使用神经元表面标记物的免疫亲和捕获实现，包括但不限于L1 CAM）或星形胶质细胞来源（通过使用星形胶质细胞表面标记物GLAST的免疫亲和捕获实现）的血液细胞外囊泡（EV）的方法。到目前为止，我们已经进行了大量的病例对照研究，测量了AD和对照受试者中EV相关的β-淀粉样蛋白、tau/p-tau、Ser和Tyr磷酸化IRS-1、突触标志物、线粒体蛋白和其他信号介质。我们已经发现了多种疾病相关的差异，对于某些蛋白质，可以有效地区分这两组。此外，生物标志物异常可能存在于临床前阶段，并可预测AD。我们最近发现，EV生物标志物预测未来的认知能力下降和未来的AD诊断在大型临床前队列从巴尔的摩老龄化纵向研究，威斯康星州老年痴呆症预防登记，和社区研究中的动脉粥样硬化风险。 该项目旨在进一步证明EV标志物与AD的其他生物标志物（特别是淀粉样蛋白和Tau PET以及MRI萎缩）之间的关系。需要这些研究来评估EV标志物的纵向变化及其在临床前阶段预测AD、跟踪疾病进展和预测从MCI向AD的转化的潜力。我们正在分析来自妇女健康倡议记忆研究-长寿研究的大型参与者队列的样本，以评估EV生物标志物与女性认知弹性和APOE e4基因型的关系。此外，我们还分析了来自印第安纳州ADRC的老年发作型AD与老年发作型AD患者的样本。在接下来的一年里，我们将使用纵向队列（哈佛衰老脑研究和CHARIOT-PRO），产生EV生物标志物测量值，并检查它们与认知能力、淀粉样蛋白和tau PET沉积、MRI萎缩和从MCI到AD痴呆的临床进展的关系。

In previous studies, our section pioneered a methodology capturing blood Extracellular Vesicles (EVs) enriched for neuronal origin (achieved by immunoaffinity capture using neuronal surface markers, including, but not limited to, L1CAM), or astrocytic origin (achieved by immunoaffinity capture using astrocytic surface marker GLAST). To date, we have conducted scores of case control studies measuring EV-associated beta-amyloid, tau/p-tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, mitochondrial proteins and other signaling mediators, in AD and control subjects. We have found multiple disease-associated differences that, for some proteins, may effectively discriminate between the two groups. In addition, biomarker abnormalities may be present at the preclinical stage and may predict AD. We recently showed that EV biomarkers predict future cognitive decline and future AD diagnosis in large preclinical cohorts from the Baltimore Longitudinal Study on Aging, the Wisconsin Registry for Alzheimer's Prevention, and the Atherosclerotic Risk in Communities studies. This project is seeking to further demonstrate the relationship between EV markers and other biomarkers for AD (especially amyloid and Tau PET, and MRI atrophy) in large preclinical cohorts. These studies are needed to assess longitudinal changes in EV markers and their potential to predict AD at the preclinical stage, track disease progression and predict conversion from MCI to AD. We are in the process of analyzing samples from a large cohort of participants in the Women's Health Initiative Memory Study - Long Life Study to assess the relationship of EV biomarkers with cognitive resilience in women and APOE e4 genotype. In addition, we have analyzed samples of individual with young-onset vs. older-onset AD from the Indiana ADRC. In the coming year, we will produce EV biomarker measurements and examine their relationship against cognitive performance, amyloid and tau PET deposition, MRI atrophy and clinical progression from MCI to AD dementia using longitudinal cohorts (Harvard Aging Brain Study and CHARIOT-PRO).