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

在之前的研究中，我们的部门开创了一种捕获血液细胞外小泡(EVS)的方法，该方法富含神经元来源(通过使用神经元表面标记，包括但不限于L1CAM，通过免疫亲和捕获实现)或星形细胞起源(通过使用星形细胞表面标记GLAST免疫亲和捕获实现)。到目前为止，我们已经进行了数十项病例对照研究，测量AD和对照组中EV相关的β-淀粉样蛋白、tau/p-tau、丝氨酸和酪氨酸磷酸化的IRS-1、突触标志物、线粒体蛋白和其他信号介质。我们发现了多种与疾病相关的差异，对于某些蛋白质来说，这些差异可能会有效地区分这两组人。此外，生物标记物异常可能出现在临床前阶段，并可能预测AD。我们最近在巴尔的摩老龄化纵向研究、威斯康星州阿尔茨海默氏症预防注册中心和社区动脉粥样硬化风险研究的大型临床前队列中表明，EV生物标记物可以预测未来的认知能力下降和未来的AD诊断。 该项目试图在大型临床前队列中进一步证明EV标记物和AD的其他生物标记物(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的潜力，跟踪疾病进展并预测从MCI到AD的转变。我们正在分析来自女性健康倡议记忆研究-长寿研究的大量参与者的样本，以评估EV生物标记物与女性认知韧性和APOE e4基因的关系。此外，我们还分析了印第安纳州ADRC的年轻AD患者和老年AD患者样本。在未来的一年里，我们将进行EV生物标记物的测量，并使用纵向队列(哈佛大学老龄化大脑研究和Chariot-PRO)来研究它们与认知能力、淀粉样蛋白和tau PET沉积、MRI萎缩以及从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).