“Chemo brain” cognitive problems linked to poor drainage of the lymphatic system

Cancer is a pretty difficult diagnosis, but many patients suffer a second blow even if they recover: “chemo brain.”

Also called “brain fog,” this mix of cognitive problems (memory problems, difficulty finding words, inability to concentrate) affects up to three in four cancer patients, according to several studies. For many, the effects last for years beyond cancer treatment.

A new study offers new models to study the causes of chemobrain and highlights the effects of chemotherapy drugs on the brain’s lymphatic system, which is a network of tiny vessels in the brain’s protective membranes that help remove waste and transport immune cells. The study was published October 13 in Communication biology.

“There is now ample evidence that these meningeal lymphatics are also involved in cognitive problems, including Alzheimer’s disease and head trauma,” said co-corresponding author Jennifer Munson, professor and director of the Fralin Biomedical Research Institute at the VTC Cancer Research Center in Roanoke. “Women are much more affected by chemobrain, or brain fog, than men when treated with very common chemotherapies, such as those routinely used on breast cancer patients.”

The study highlights considerations for cancer treatment beyond eradicating the cancer itself, said Monet Roberts, assistant professor of biomedical engineering and co-corresponding author of the paper.

“Our study is important because it explores a very real, hidden layer of chemotherapy treatment that leaves lasting scars in the daily lives of those who live with or have survived their cancer journey,” said Roberts, a former postdoctoral associate who trained in Munson’s lab at the Fralin Biomedical Research Institute and who now continues to study the lymphatic system in her own lab.

Munson and his team developed a three-tiered modeling system, using a combination of mouse models and tissue-engineered tissues, to study changes in the lymphatic system. The in vitro model is the first human tissue engineering system that replicates this unique tissue and offers the potential for therapeutic testing, patient-specific analyses, and disease-specific incorporation.

The study looked at the effects of two of the most common chemotherapy drugs, docetaxel and carboplatin. Although both showed impacts on the lymphatic system, they were much more pronounced with docetaxel.

“What we’re seeing is a narrowing of the lymphatic vessels and fewer loops or branches in the vessels,” said Munson, who is also a professor in Virginia Tech’s department of biomedical engineering and mechanics. “These are signs of reduced growth that indicate the lymphatics are changing or not regenerating in beneficial ways. Lymphatic health actually declined in all three models measured in different ways.”

As expected, brain imaging showed reduced drainage of the lymphatic system in mice. When the research team performed cognitive tests, they found that if a mouse had been treated with docetaxel, it had poor memory.

Taken together, Munson said, the findings suggest that chemo brain could result from poor drainage of the lymphatic system in response to chemotherapy.

“This could potentially explain some of these memory deficits, similar to what we’ve seen in Alzheimer’s disease,” Munson said.

“The first step is knowing,” she said. “And now the hope is to figure out how to help. Could giving a pharmaceutical, like a protein, alleviate the problem and not interfere with chemotherapy? We also know about other things that affect brain flow, like better sleep and exercise.”

Munson also wants to explore gender differences in the prevalence of chemobrain.

“Lymphatic diseases generally affect women more than men,” she said. “We are extremely interested in trying to understand this difference and why this difference might exist.”

“Ultimately, this work highlights the need to consider not only survival, but also the often overlooked long-term neurological side effects of cancer treatment on cognitive well-being and quality of life,” Roberts said, “particularly among women who are disproportionately affected by these lasting side effects.”