Brain-derived extracellular vesicle (BDEV) abundance and BDEV protein associations with clinical phenotypes and treatment response in untreated first-episode psychosis.

Authors

Lusi Zhang, Adam M Lee, Zia L Maxim, Manjula Munirathinam, Bart S Larsen, Michael K Georgieff, Sarah K Keedy, James L Reilly, John A Sweeney, Phu V Tran, Jeffrey R Bishop

Published in

Brain, behavior, and immunity. Pages 106912. Jul 12, 2026. Epub Jul 12, 2026.

Abstract

Reliable biomarkers that capture central nervous system (CNS) processes during the earliest stages of psychosis remain critically needed for more effective early treatment and monitoring response to therapy. Brain-derived extracellular vesicles (BDEVs) that traverse the blood-brain barrier (BBB) can be isolated from peripheral blood, thereby offering a novel and minimally invasive approach to quantify CNS molecular biomarkers. We hypothesized that BDEV abundance and BDEV neuroinflammatory and neurotrophic protein cargo would differ between individuals with first-episode psychosis (FEP) and healthy controls (HCs), reflecting altered neuroinflammatory processes and vesicle trafficking associated with psychosis and clinical outcomes. In a cohort of antipsychotic-naïve individuals with FEP (n = 57) and HCs (n = 28), BDEVs were isolated from serum. Luminex assays quantified concentrations of brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B), and C-reactive protein (CRP), in BDEVs and serum. A subset of FEP participants (n = 34) subsequently completed four weeks of antipsychotic treatment. Group differences in BDEV characteristics, protein measures, and their associations with diagnosis, baseline symptoms, and four-week symptom change were quantified. FEP participants showed a trend toward higher BDEV concentration than HCs (median 14.0x10⁹ versus 10.2x10⁹ particles/mL, p = 0.052), and higher baseline BDEV concentrations were significantly associated with more severe pretreatment symptoms (β = 4.09x10^-10, p = 0.003) and greater symptom improvement after four-week antipsychotic treatment (β = 3.29x10^-10, p = 0.029). Within BDEVs, BDNF (β = -1.05; p = 0.002) and CRP (CRP; β = -0.84; p = 0.002) were significantly reduced in FEP vs HC, with a trend for S100B (β = -0.57; p = 0.061). In contrast, serum protein levels showed no case-control differences and did not correlate with BDEV cargo. Lower baseline BDEV BDNF, S100B, and CRP predicted greater therapeutic response in males. BDEVs offer a minimally invasive window into CNS-specific biology in early psychosis. BDEV abundance and neuroinflammatory/neurotrophic cargo concentrations show illness-severity and sex-dependent associations not detectable in serum, supporting their potential as biomarkers for early pathophysiology and treatment response in FEP.

PMID:
42437583
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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