Dataset Information

Imaging the transmembrane and transendothelial sodium gradients in gliomas.

ABSTRACT: Under normal conditions, high sodium (Na⁺) in extracellular (Na⁺_e) and blood (Na⁺_b) compartments and low Na⁺ in intracellular milieu (Na⁺_i) produce strong transmembrane (ΔNa⁺_mem) and weak transendothelial (ΔNa⁺_end) gradients respectively, and these manifest the cell membrane potential (V_m) as well as blood-brain barrier (BBB) integrity. We developed a sodium (²³Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure ΔNa⁺_mem and ΔNa⁺_end. In vitro ²³Na-MRSI established that the ²³Na signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo ²³Na-MRSI showed Na⁺_i remained unshifted and Na⁺_b was more shifted than Na⁺_e, and these together revealed weakened ΔNa⁺_mem and enhanced ΔNa⁺_end in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened ΔNa⁺_mem (i.e., depolarized V_m) implying an aggressive state for proliferation, whereas RG2 tumors displayed elevated ∆Na⁺_end suggesting altered BBB integrity. We anticipate that ²³Na-MRSI will allow biomedical explorations of perturbed Na⁺ homeostasis in vivo.

SUBMITTER: Khan MH

PROVIDER: S-EPMC7987982 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Imaging the transmembrane and transendothelial sodium gradients in gliomas.

Khan Muhammad H MH Walsh John J JJ Mihailović Jelena M JM Mishra Sandeep K SK Coman Daniel D Hyder Fahmeed F

Scientific reports 20210323 1

Under normal conditions, high sodium (Na+) in extracellular (Na+e) and blood (Na+b) compartments and low Na+ in intracellular milieu (Na+i) produce strong transmembrane (ΔNa+mem) and weak transendothelial (ΔNa+end) gradients respectively, and these manifest the cell membrane potential (Vm) as well as blood-brain barrier (BBB) integrity. We developed a sod ...[more]

PMID: 33758290

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Project description:INTRODUCTION:Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively. METHODS:We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns. RESULTS:Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113). CONCLUSION:This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required.

Dataset Information

Imaging the transmembrane and transendothelial sodium gradients in gliomas.

Publications

Imaging the transmembrane and transendothelial sodium gradients in gliomas.

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