# In vivo spatiotemporal mapping of proliferation activity in gliomas via water-exchange dynamic contrast-enhanced MRI

## TL;DR

This study introduces a non-invasive MRI method to map tumor cell growth in gliomas by tracking water movement, offering a more accurate and easier way to monitor treatment response.

## Contribution

A novel, non-invasive MRI technique using water-exchange dynamics to map glioma proliferation activity with high accuracy.

## Key findings

- The water-efflux rate (kio) measured by MRI accurately reflects glioma cell proliferation in culture and in vivo.
- kio outperforms multimodal MRI and machine learning in predicting tumor proliferation activity.
- AQP4 is identified as a key molecule linking water transport to proliferation activity in gliomas.

## Abstract

Proliferation activity mapping is crucial for the guidance of first biopsy and treatment evaluation of gliomas due to the highly heterogenous nature of glioma tumor. Here we propose and demonstrate an ease-of-use way of in vivo spatiotemporal mapping of proliferation activity by simply tracking transmembrane water dynamics with magnetic resonance imaging (MRI). Specifically, we demonstrated that proliferation activity can accelerate the transmembrane water transport in glioma cells.

Method: The transmembrane water-efflux rate (kio) measured by water-exchange dynamic contrast-enhanced (DCE) MRI. Immunofluorescence, immunohistochemistry, and immunocytochemistry staining were used to validate results obtained from the in vivo imaging studies.

Results: In glioma cell cultures, kio precisely followed the dynamic changes of proliferation activity in growth cycles and response to temozolomide (TMZ) treatment. In both animal glioma model and human glioma, kio linearly and strongly correlated with the spatial heterogeneity of intra-tumoral proliferation activity. More importantly, proliferation activity predicted by the single MRI parameter kio is much more accurate than those predicted by state-of-the-art methods using multimodal standard MRIs and advanced machine learning. Upregulated aquaporin 4 (AQP4) expression were observed in most proliferating glioma cells and the knockout of AQP4 could largely slow down proliferation activity, suggesting AQP4 is the potential molecule connecting MRI-kio with proliferation activity.

Conclusion: This study provides an ease-of-use, accurate, and non-invasive imaging method for the spatiotemporal monitoring of proliferation activity in glioma.