Non‐Invasive, High‐Resolution ( ¹ H ₂ O) Metabolic Activity Diffusion Imaging [MADI] of Rat Glioma

We have recently developed a metabolic activity imaging approach entitled Metabolic Activity Diffusion Imaging [MADI] which utilizes diffusion weighted MRI to quantify k_io, the homeostatic cellular H₂O efflux rate constant without the use of contrast agents, thus enabling measurement in both normal and tumor brain regions. Importantly, k_io 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 k_ioV and k_ioVρ products, which convert the k_io 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 SUV_max substantially increased while tumor k_ioV substantially decreased versus contralateral. Edematous peritumoral regions indicated substantially higher k_ioV values than contralateral. The k_io values tended to be moderately higher than contralateral. Similarly, the k_ioVρ 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 [SUV_max] 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.