# Non‐Invasive, High‐Resolution (1H2O) Metabolic Activity Diffusion Imaging [MADI] of Rat Glioma

## TL;DR

A new MRI technique called MADI measures water movement in rat brain tumors without contrast agents, offering high-resolution metabolic insights.

## Contribution

MADI introduces a non-invasive method to quantify cellular water efflux and related metabolic parameters in brain tumors.

## Key findings

- Tumor kioV values were significantly lower than contralateral regions, indicating reduced water efflux per cell.
- MADI showed higher resolution and contrast compared to 18FDG-PET in detecting tumor metabolic activity.
- Tumor glycolysis contributed minimally to overall energy production based on the water-glucose index (WGI).

## Abstract

We have recently developed a metabolic activity imaging approach entitled Metabolic Activity Diffusion Imaging [MADI] which utilizes diffusion weighted MRI to quantify kio, the homeostatic cellular H2O efflux rate constant without the use of contrast agents, thus enabling measurement in both normal and tumor brain regions. Importantly, kio quantifies transmembrane water cycling, a significant proportion of which is coupled to Na+/K+ ATPase activity and associated cellular energy utilization, hence constituting a key metabolic biomarker. MADI also quantifies the cell volume (V), and cell density (ρ); these enable quantification of the kioV and kioVρ products, which convert the kio rate constant to rates of water efflux per cell (units: pL/s/cell) and per tissue (units: pL/s/uL [tissue]), respectively. Representing its first application to brain cancer, MADI was comprehensively evaluated at high field (11.75 T) in rats implanted with syngeneic RG2 brain tumors, and in non‐tumor bearing rats. 18FDG‐PET images were obtained the following day for comparison with a commonly utilized metabolic imaging modality. A subset of rats were subsequently treated with temozolamide and radiation. Tumor 18FDG‐PET SUVmax substantially increased while tumor kioV substantially decreased versus contralateral. Edematous peritumoral regions indicated substantially higher kioV values than contralateral. The kio values tended to be moderately higher than contralateral. Similarly, the kioVρ tended to increase only moderately in tumor versus contralateral suggesting that the marked glycolytic activation did not substantially increase overall tissue energy production. Furthermore, the ratio of cellular water efflux to glucose uptake (WGI), suggested that tumor glycolysis remained a minor contributor to overall energy production. Mean tumor size, MADI tumor parameters, and 18FDG‐PET [SUVmax] were not significantly altered with treatment. The MADI ρ was compared with that observed from a 3D confocal histological analysis. Our study supports the potential utility of the novel cytometric and metabolic MADI parameters in cancer detection and assessment.

We employed Metabolic Activity Diffusion Imaging [MADI] and 18FDG‐PET in rats with syngeneic RG2 glioblastoma brain tumors. MADI quantifies kio (the cellular H2O efflux rate constant), cell volume (V), and cell density (ρ), without the use of contrast agents. The kioV product quantifies the rate of water efflux per cell. The kioV was substantially decreased in tumors and demonstrated superior image resolution compared with 18FDG‐PET. We conclude that MADI has potential utility for cancer assessment.