Peripheral Signatures of Multidimensional Pathology in Symptomatic and Asymptomatic Creutzfeldt-Jakob Disease

Plasma markers of neuronal injury in Creutzfeldt-Jakob disease (CJD) are established, but peripheral biomarkers reflecting glial activation, synaptic dysfunction, and vascular impairment remain less explored. We systematically assessed these markers in symptomatic CJD and asymptomatic PRNP mutation carriers to improve diagnosis and identify early pathophysiology.

This prospective cohort study recruited CJD, frontotemporal dementia (FTD), healthy controls (HCs), and preclinical familial CJD pedigrees. Sixteen plasma proteins representing neuronal injury, glial activation, synaptic function, and vascular/BBB integrity were measured. Analyses included group differences, discriminative performance, clinical/imaging correlations, and longitudinal trajectories.

We enrolled 130 CJD patients, 145 FTD, 70 HCs, 16 asymptomatic PRNP carriers (4-6 years follow-up, 4 converters), and 16 non-carrier family controls. In symptomatic CJD, plasma NfL, t-tau, and GFAP were strongly elevated, each showing excellent discriminative performance (AUCs > 0.93 vs. HCs and > 0.82 vs. FTD). We also observed alterations in vascular/BBB markers, with VCAM-1 levels elevated and significantly associated with both clinical decline and DWI hyperintensity. In asymptomatic carriers, biomarker levels remained largely normal and stable preclinically. Notably, two G114V carriers showed mild pre-symptomatic elevations in NfL and GFAP, and one exhibited a slight VCAM-1 increase before clinical onset; all changes exceeded the 90th percentile of control values. E200K and T188K carriers showed no pre-onset changes.

Plasma biomarkers in CJD may reflect multisystem involvement, with neuronal markers showing strong discriminative potential and vascular proteins indicating possible BBB dysfunction. In asymptomatic carriers, minor changes may occur only near onset in those with relatively slow-progressing mutations.