Memory lapses, difficulty concentrating, and a sense of mental cloudiness—often referred to as “chemo brain”—affect as many as 75% of cancer patients and can last long after treatment ends. Now, researchers at the Fralin Biomedical Research Institute at VTC have found evidence that these cognitive issues may stem from disruptions in the brain’s lymphatic system caused by chemotherapy. The study, published in Communications Biology, provides a new avenue to study and potentially mitigate these long-term neurological side effects of chemotherapy.
“Our study is important because it explores a very real, hidden layer of chemotherapy treatment that leaves lasting scars on the daily lives of those who are living with or have survived in their cancer journey,” said co-lead author Monet Roberts, PhD, an assistant professor of biomedical engineering at the Fralin Biomedical Research Institute.
The brain’s lymphatic system, known as the meningeal lymphatics, consists of a network of vessels embedded in the protective layers of the brain. These vessels drain cerebrospinal fluid and interstitial waste from the central nervous system (CNS) to the cervical lymph nodes, which helps maintain immune surveillance. Previous studies have also implicated meningeal lymphatics in other neurological conditions such as Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, and brain tumors.
For their research, the Fralin team developed two different study models, a human cell-based in vitro model and an ex vivo mouse meningeal layer culture. Using the results from their tests in these two systems, the team then correlated their findings via in vivo imaging and behavioral analysis in mice. The researchers tested carboplatin and docetaxel, two commonly used chemotherapy drugs and showed that docetaxel, in particular, led to significant structural changes in the meningeal lymphatic vessels, including reduced vessel branching and shrinking.
“What we see is a shrinking of the lymphatic vessels, and fewer loops or branches in the vessels,” said senior author Jennifer Munson, PhD, a professor and director of the Fralin Biomedical Research Institute’s Cancer Research Center. “These are signs of reduced growth that indicate the lymphatics are changing, or not regenerating, in beneficial ways. Lymphatic health really declined across all three models measured in different ways.”
Behavioral tests in mice treated with docetaxel showed impaired cognitive performance, including diminished memory function. “From our results, we showed decreased novel object recognition memory function and increased latency in docetaxel-treated mice compared to saline treatment,” the researchers wrote. “The decreased meningeal lymphatic features, particularly intussusceptions/loops, observed in docetaxel-treated mice were also strongly correlated with some of the memory deficits in mice.”
While docetaxel does cross the blood-brain barrier in its original form, this new research suggests that it can affect meningeal lymphatics by building up in the dural layers that house the meningeal lymphatics, potentially leading to long-term structural and functional impairments. Further, “Docetaxel has been associated with increased incidence of breast cancer metastasis to the brain, suggesting its potential to disrupt the (blood-brain barrier) and cause other forms of dysregulation in the CNS,” the researchers wrote.
Notably, this study also indicated that carboplatin did not significantly alter lymphatic structure or impair cognition, suggesting that the incidence of chemo brain could be confined to only certain chemotherapies, in particular those that have an impact on lymphatic tissue.
The current research builds on earlier work by the Fralin team that uncovered how chemotherapy can affect lymphatic vessels in other parts of the body, such as the mammary fat pads and mesentery.
Via their development of the first in vitro human tissue-engineered model of the meningeal lymphatic system, the researchers said it can serve as a new platform for preclinical therapeutic testing and drug screening. This could eventually provide a way for researchers to predict or test patient-specific responses to chemotherapies.
This could be particularly important for the future treatment of breast cancer using chemotherapy. “Women are affected by chemo brain, or brain fog, much more than men when treated by very common chemotherapies, such as those used on breast cancer patients on a regular basis,” said Munson. For this reason, the Fralin researchers plan new studies aimed at better understanding how differences in the lymphatic systems between women and men might influence susceptibility to chemo brain.
“Ultimately, this work underscores the need to consider not only survival, but also the long-term, often overlooked neurological side effects of cancer treatment on cognitive well-being and quality of life,” Roberts said. “Especially in women who are disproportionately affected by these lasting side effects.”
Through ongoing research, the investigators are hopeful that interventions can be developed that address these effects on lymphatic system either during or after chemotherapy.
“The first step is knowing,” Munson said. “And now the hope is to figure out how to help. Could delivering something pharmaceutically, such as a protein, alleviate the problem and not interfere with the chemotherapy?”
