Multimodal evidence for impaired glymphatic brain clearance as a mediator of "inflammaging" in schizophrenia - integrating insights from in vivo neuroimaging, omics, and post-mortem single nucleus-RNA-Seq data
- 1Shengjing Hospital of China Medical University, Shenyang, China
Abstract
Persistent cognitive impairment and reduced life expectancy in schizophrenia may arise from inflammation-driven accelerated aging ("inflammaging"), yet the underlying mechanisms remain unclear. Impaired glymphatic clearance, dependent on polarized aquaporin-4 (AQP4) localization at astrocytic endfeet, offers a plausible mechanistic link between inflammation and brain aging. Here, we integrate in vivo neuroimaging with post-mortem single-nucleus transcriptomics from distinct patient cohorts to demonstrate glymphatic dysfunction in schizophrenia and define its molecular basis. We identify reduced astrocytic expression of components of the dystrophin-associated protein complex (SNTA1, DAG1) required for AQP4 polarization. Both in vivo neuroimaging and post-mortem gene expression signatures of glymphatic dysfunction are restricted to an inflammatory subgroup characterized by peripheral immune activation and pro-inflammatory glial transcriptional profiles. Moreover, imaging signatures of glymphatic impairment are associated with schizophrenia polygenic risk scores enriched for immune - and oxidative stress - related aging pathways as well as cognitive dysfunction. At the cellular level, glymphatic dysfunction coincides with loss of homeostatic programs in microglia and astrocytes, increased inflammatory signaling, and endothelial signatures of blood-brain barrier disruption. Across modalities, glymphatic impairment is linked to accelerated aging, including increased brain and epigenetic age, and aging-related gene expression signatures.
Related
- Multimodal Brain Graph Analysis for Uncovering Path-Based Biomarkers in Schizophrenia: Integrating Static and Dynamic Approaches.
- A Test for Confounding in Coupling of Multimodal Neuroimaging Data
- Multimodal imaging maps spinal glymphatic transport in health and its disruption after injury
- The SWAN atlas: an open multimodal resource combining neuroimaging and high-resolution histology of the human brain in stereotactic space
- A Multimodal Neuroimaging Study of Hyperlipidemia-Induced Abnormal Spontaneous Brain Activity and Cognitive Decline.
BibTeX
@misc{tan2026multimodal,
title = {{Multimodal evidence for impaired glymphatic brain clearance as a mediator of "inflammaging" in schizophrenia - integrating insights from in vivo neuroimaging, omics, and post-mortem single nucleus-RNA-Seq data}},
author = {X. Tan and M. Simon and D. Rosebrock and M. Firuleva and D. Gruber-Schoffnegger and M. Fuerst and R. Aldisi and S. Heilmann-Heimbach and K. Bechter and G. Schnellbaecher and T. Frodl and K. Mathiak and A. J. Gaebler},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.753662},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.753662v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Multimodal evidence for impaired glymphatic brain clearance as a mediator of "inflammaging" in schizophrenia - integrating insights from in vivo neuroimaging, omics, and post-mortem single nucleus-RNA-Seq data
AU - X. Tan
AU - M. Simon
AU - D. Rosebrock
AU - M. Firuleva
AU - D. Gruber-Schoffnegger
AU - M. Fuerst
AU - R. Aldisi
AU - S. Heilmann-Heimbach
AU - K. Bechter
AU - G. Schnellbaecher
AU - T. Frodl
AU - K. Mathiak
AU - A. J. Gaebler
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.753662
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.753662v1
AB - Persistent cognitive impairment and reduced life expectancy in schizophrenia may arise from inflammation-driven accelerated aging ("inflammaging"), yet the underlying mechanisms remain unclear. Impaired glymphatic clearance, dependent on polarized aquaporin-4 (AQP4) localization at astrocytic endfeet, offers a plausible mechanistic link between inflammation and brain aging. Here, we integrate in vivo neuroimaging with post-mortem single-nucleus transcriptomics from distinct patient cohorts to demonstrate glymphatic dysfunction in schizophrenia and define its molecular basis. We identify reduced astrocytic expression of components of the dystrophin-associated protein complex (SNTA1, DAG1) required for AQP4 polarization. Both in vivo neuroimaging and post-mortem gene expression signatures of glymphatic dysfunction are restricted to an inflammatory subgroup characterized by peripheral immune activation and pro-inflammatory glial transcriptional profiles. Moreover, imaging signatures of glymphatic impairment are associated with schizophrenia polygenic risk scores enriched for immune - and oxidative stress - related aging pathways as well as cognitive dysfunction. At the cellular level, glymphatic dysfunction coincides with loss of homeostatic programs in microglia and astrocytes, increased inflammatory signaling, and endothelial signatures of blood-brain barrier disruption. Across modalities, glymphatic impairment is linked to accelerated aging, including increased brain and epigenetic age, and aging-related gene expression signatures.
ER -