This preclinical study developed PET imaging strategies to detect the procoagulant state (cerebral microthrombi) in TgCRND8 Alzheimer's disease (AD) mice using fibrin-binding (FBP) and platelet-targeting (Thrombo-tag/CD41) radiotracers, and validated findings against post mortem brain tissue from 39 human AD patients.
Fibrin-targeted PET ([89Zr]Zr-DFO-FBP and [68Ga]Ga-DOTA-TZ pre-targeting) showed significantly higher brain uptake in AD vs. wild-type (WT) mice at 24 hours (Cohen's d up to 1.39 by voxel-wise analysis). Platelet-targeted Thrombo-tag PET showed robust AD vs. WT differences (Cohen's d = 0.97 whole brain; ex vivo biodistribution Cohen's d = 0.93, p = 0.001), with signal increasing with age in cortex (ρ = 0.55, p = 0.034) and hippocampus (R = 0.73, p = 0.002). In human AD post mortem cortex (N = 39), cerebral platelet (CD41) content correlated significantly with fibrin burden (Spearman's ρ = 0.343, p = 0.033); ~49% of AD patients showed abnormal cerebral fibrin. AD cases with fibrin had 2× the platelet density of fibrin-negative cases (21.4 vs. 10.7 platelets/mm², Cohen's d = 2.24, p = 0.009).
- All PET imaging was performed in a transgenic mouse model (TgCRND8); clinical translation requires disease-specific radiotracer uptake thresholds not yet established. - FBP is a small peptide with high renal clearance and preferentially binds newly formed rather than mature thrombi, potentially underestimating total fibrin burden; it also has limited brain parenchymal penetration. - Human post mortem cohort (N = 39, 85% female, mean age 87 years) is small, limiting generalizability of associations with clinical variables.
About half of AD patients harbor a procoagulant state (cerebral fibrin/platelet deposition) that is currently undiagnosed in vivo; these novel PET biomarkers—particularly the platelet-targeting Thrombo-tag—could eventually stratify patients for anticoagulant, antiplatelet, or fibrin-targeted immunotherapy, but require clinical validation before use.
Explore related topics
