Stephanie Yang, Andrew A. Lin, Hanfei Shen, Laura W. Pappalardo, Griffin B. Spychalski, Jean G. Rosario, Leah K. Forsberg, Kiera M. Grant, Joshua R. Buser, Rodolfo Savica, Sid O’Bryant, David Cecil Jones, Dennis W. Dickson, R. Ross Reichard, Aivi T. Nguyen, David F. Meaney, Bradley F. Boeve, Owen Ross, Pamela J. McLean, David Issadore
Identifying plasma-based biomarkers that can accurately differentiate Lewy body disease (LBD) from Alzheimer's disease (AD) remains a major challenge. Extracellular vesicles (EVs), which carry molecular cargo from their parent cells and can cross the blood-brain barrier, offer a new path forward. We developed the multiplexed Track-Etch magnetic NanoPOre (mTENPO) platform, a highly parallelized microfluidic technology for cell-specific EV isolation, and demonstrated independent enrichment of GluR2+ (neuron-derived) and GLAST+ (astrocyte-derived) EVs from the antemortem plasma of 137 autopsy-confirmed LBD, AD, mixed pathology, and control subjects. By integrating miRNA sequencing of GluR2+ and GLAST + EV cargo with plasma measurements of Aβ40, Aβ42, tau, p-Tau181, and p-Tau231, we identified a multimodal 15-feature panel that more comprehensively reflects brain pathology than conventional biomarkers. Using tenfold cross-validation to mitigate overfitting, the panel achieved an accuracy of 0.95 and an area under the curve of 0.96 for distinguishing LBD versus AD.