2026 ECNP Congress

PS02-2164

Exploring cellular, neuroinflammatory and neurotransmitter-based mechanisms of blood-brain barrier leakage in schizophrenia-spectrum disorders

Karolina Piasecka — R. Troyas, V. Yakimov, A. Weinhold, E. Boudriot, P. Falkai, D. Keeser, A. Schmitt, J. Moussiopoulou, L. Röll · LMU University Hospital, Department of Psychiatry and Psychotherapy, Munich, Germany

2026 ECNP Congress

Our previous work demonstrated increased blood-brain barrier (BBB) leakage in a subgroup of schizophrenia-spectrum disorders (SSD) patients [1], yet the mechanisms underlying this finding remain unclear. Astrocytes and microglia are implicated in SSD pathophysiology [2], and given their central role in maintaining BBB integrity, even mild neuroinflammation may affect their function - representing a plausible mechanistic link to BBB leakage. Disrupted BBB may in turn allow peripheral immune cells and pro-inflammatory molecules to enter the central nervous system, further disrupting the microenvironment necessary for normal synaptic function. SSD has furthermore been consistently associated with alterations across multiple neurotransmitter systems, including dopaminergic, serotonergic, and cholinergic pathways [3], raising the question of whether the spatial distribution of BBB leakage corresponds to these systems. Imaging transcriptomics links spatial neuroimaging patterns to brain-wide gene expression data, and neurotransmitter receptor mapping offers complementary insight into the neurochemical context of these regions - together providing a practical framework to explore such relationships in vivo.

In this study, we aimed to explore the potential cellular and neurotransmitter-based underpinnings of increased BBB leakage in SSD, by using (1) imaging transcriptomics to examine spatial correspondence between BBB leakage and cell-type-specific gene expression, and (2) neurotransmitter receptor mapping to examine spatial overlap with major neurotransmitter systems.

BBB leakage was assessed using dynamic contrast-enhanced magnetic resonance imaging in 81 individuals with SSD and 52 age- and sex-matched healthy controls. Voxel-wise Ktrans maps were derived using Patlak modelling, and group differences were examined via voxel-wise ANCOVA controlling for relevant demographic covariates. Gene expression data from the Allen Human Brain Atlas [4] were parcellated using the Brainnetome atlas and spatially correlated with the Ktrans map. Gene-level correlation values served as input for gene set enrichment analysis [5] targeting cell-type-specific gene sets. PET-derived maps from the neuromaps toolbox were used for neurotransmitter receptor mapping and spatially correlated with the statistical Ktrans maps.

In SSD, brain regions with increased BBB leakage showed positive enrichment (q < 0.05) for astrocyte, microglia, endothelial, and oligodendrocyte gene sets, and negative enrichment for neuronal gene sets. Spatial overlap between regions with increased BBB leakage and PET-derived neurotransmitter maps revealed positive correlations with dopaminergic, serotonergic, cholinergic, noradrenergic, and glutamatergic systems. Interestingly, a negative correlation with 5-HT2A receptors was detected.

Our findings suggest that BBB leakage in SSD spatially co-localises with regions enriched in glial and vascular gene expression and corresponding to the distribution of monoaminergic, cholinergic, and glutamatergic systems. While not establishing any causal mechanisms, this study refines mechanistic hypotheses and supports targeting glial–vascular pathways in future studies of BBB dysfunction in SSD. Astrocyte-targeted PET imaging, patient-derived transcriptomic profiling stratified by BBB leakage status, and iPSC-based glial models can provide platforms for verifying these hypotheses. Taken together, the presented exploratory multimodal approach provides a hypothesis-generating framework for linking in vivo BBB dysfunction to cellular and neurochemical alterations in SSD.

References

  1. Moussiopoulou, J., Yakimov, V., Roell, L., Rauchmann, B., Toth, H., Melcher, J., Jäger, I., Lutz, I., Kallweit, M. S., Papazov, B., Boudriot, E., Seelos, K., Dehsarvi, A., Campana, M., Raabe, F., Maurus, I., Löhrs, L., Brendel, M., Stöcklein, S., . . . Wagner, E. (2025). Higher blood–brain barrier leakage in schizophrenia-spectrum disorders: A comparative dynamic contrast-enhanced magnetic resonance imaging study with healthy controls. Brain Behavior and Immunity, 128, 256–265. https://doi.org/10.1016/j.bbi.2025.04.003
  2. Khandaker, G. M., Cousins, L., Deakin, J., Lennox, B. R., Yolken, R., & Jones, P. B. (2015). Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. The Lancet Psychiatry, 2(3), 258–270. https://doi.org/10.1016/s2215-0366(14)00122-9
  3. Owen, M. J., Sawa, A., & Mortensen, P. B. (2016). Schizophrenia. The Lancet, 388(10039), 86–97. https://doi.org/10.1016/s0140-6736(15)01121-6
  4. Hawrylycz, M. J., Lein, E. S., Guillozet-Bongaarts, A. L., Shen, E. H., Ng, L., Miller, J. A., Van De Lagemaat, L. N., Smith, K. A., Ebbert, A., Riley, Z. L., Abajian, C., Beckmann, C. F., Bernard, A., Bertagnolli, D., Boe, A. F., Cartagena, P. M., Chakravarty, M. M., Chapin, M., Chong, J., . . . Jones, A. R. (2012). An anatomically comprehensive atlas of the adult human brain transcriptome. Nature, 489(7416), 391–399. https://doi.org/10.1038/nature11405
  5. Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., & Mesirov, J. P. (2005). Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences, 102(43), 15545–15550. https://doi.org/10.1073/pnas.0506580102