Yale News

In a paper published in Scientific Reports last week, Yale researchers presented their development of a new sodium magnetic resonance spectroscopic imaging, or MRSI, method that will help detect gliomas, a type of brain tumor, in a non-invasive way.

Led by graduate student Muhammad Khan GRD ’22 and professor of biomedical engineering and radiology and biomedical imaging Fahmeed Hyder, researchers at the School of Engineering and Applied Science studied tumor microenvironments in rats and developed a breakthrough technique — their MRSI method — for cancer research. Although traditional screening methods look for molecules specifically present in tumors, which requires invasive procedures, Khan and Hyder took a different approach, which involves the distribution of sodium in the brain and could have broader implications for tumor detection.

“The cool thing about this study is that it’s using information that a lot of other researchers have gravitated away from in the past decade or so,” Khan said. “A lot of cancer research lately has been looking at tumor-specific molecules. And even in the imaging sphere, a lot of it has been reliant on the proton signal. But there’s other information, like the salt distribution, that can be analyzed.”

According to Hyder, cells survive in an intricate environment that must be maintained for proper cell function. With healthy cells, sodium concentration is low inside the cell and high outside the cell. This produces a strong transmembrane sodium gradient that is responsible for many bodily functions, such as maintaining blood pressure. Hyder explained that the concentration difference also produces a weak transendothelial sodium gradient that helps maintain the blood-brain barrier — the border of endothelial cells that prevents certain substances from crossing into the extracellular fluid of the central nervous system where neurons reside.

Thus, maintaining proper sodium concentrations at different locations in the brain — in the cells, outside the cells and in the blood — is essential. When tumor cells form, this concentration difference is disrupted, along with other factors like pH, which is an indicator of proton concentration.

“When a tumor mass forms, cells disrupt this gradient, as sodium is brought into the cells and protons are pushed out,” Hyder said. “This sodium imbalance will then cause surrounding cells to become tumor-like, which will further alter the surrounding environment. It’s like a feedback loop of tumor growth. Thus, the environment of cells is an indication of what’s happening physiologically.”

According to the researchers, the reason for this disruption is that cancer slows down the infected cell’s metabolism and the production of ATP within it — ATP production helps restore sodium concentrations in normal cells to maintain the transmembrane gradient.

Current MRI techniques can only detect the total amount of sodium in the brain, rather than the exact location of the substance inside or outside of the cell. But Khan and Hyder were able to develop a new magnetic resonance spectroscopy technique that compartmentalizes the sodium MRI signal and shows the sodium distribution in the brain. In their paper, they successfully imaged tumors in rat brains using this technique.

Although the idea to use sodium to image brain tumors is not new, previous researchers have been unsuccessful in developing a technique to carry it out, according to Hyder.

The key to Khan and Hyder’s technique is the use of the chemical compound and paramagnetic sensor TmDOTP5-, which is injected into the bloodstream of the rats prior to imaging. This compound is unable to cross the cell membrane, thus maintaining the concentration difference between the inside and outside of the cell. TmDOTP5- also attracts sodium ions and produces different sodium MRI signals based on how much sodium it attracts in a specific location. This allows for scientists to see the sodium distribution in the tumors in vivo, and in a non-invasive way — which Hyder calls a “breakthrough.”

“Quantifying variations of these … sodium concentration gradients in different tumors, and I think more importantly during therapy, has crucial clinical potential since imaging methods such as standard MRI, CT or PET have shown no or very limited capabilities to assess this biochemical information,” assistant professor of radiology at NYU Grossman School of Medicine Guillaume Madelin wrote in an email to the News.

In the future, the researchers hope to investigate more questions regarding tumor microenvironments. For example, are the events that are changing the pH environment synonymous with the events that are changing the sodium environment? Hyder and Khan believe they may be related and seek to explore the question further.

The new MRSI technology also has applications in other brain diseases that are characterized by chemical imbalances. Further, it can be used not only to detect tumors, but to monitor and guide the cancer treatment.

“We didn’t do this work or start in this direction completely in a vacuum,” Khan said. “There were other researchers who provided us with inspiration for this work. And I’m sure that whether it be me or someone else, the findings from this study will be able to serve as a platform for subsequent experiments to further our understanding of cancer.”

According to Mayo Clinic, gliomas are one of the most common types of primary brain tumors.

Veronica Lee | veronica.lee@yale.edu