Chemotherapy is essential for many cancer patients, but some suffer from cognitive impairment throughout treatment. “Chemobrain” can consist of memory, attention, and executive function deficits.
Preventing chemobrain. A leak of calcium through the brain's ryanodine receptor (above) led to neurocognitive dysfunction in mice treated with cancer chemotherapy. Mice are protected from “chemobrain” when the RY3&4 domain (pink) is positioned above, preventing the leak. Image credit: Yang Liu and Andrew Marks / Columbia University.
A new study now reveals that “chemobrain” may be caused by an excess of calcium floating around inside cells. The research, from investigators at Columbia University Vagelos College of Physicians and Surgeons and the University of Texas MD Anderson Cancer Center, could lead to new treatments to restore cognition in patients experiencing symptoms.
Calcium serves as a crucial messenger in cells throughout the body and enables us to think, move, and process nutrients. But as with any good thing, calcium only works well in moderation.
Calcium is controlled by ryanodine receptors that lie inside cells and control the amount of calcium in the cell. But sometimes the receptors get stuck in the open position, allowing too much calcium to flow inside cells uncontrolled.
Chemobrain – abstract artistic impression. Image credit: Moritz Kindler via Unsplash, free license
This leak of calcium was first discovered in heart failure but has also been linked to cognitive decline that accompanies heart failure, post-traumatic stress disorder, long COVID, and Alzheimer’s, based on findings from the lab of Andrew Marks, MD, chair and professor of physiology & cellular biophysics at VP&S and co-senior author of the new study.
When the NIH announced an initiative to fund research on the understudied phenomenon of chemotherapy-induced cognitive impairment, Marks and his collaborator, endocrinologist Theresa Guise, MD, of MD Anderson, decided to investigate whether calcium leaks could be responsible for this type of cognitive impairment as well.
The team tested the idea in mice and found that a chemotherapy treatment causes calcium leaks in the brain and neurocognitive dysfunction in mice with breast cancer and in healthy mice. The leaked calcium inside cells, the team found, impairs neuronal function.
A brain 3D model – illustrative photo. Image credit: Lisa Yount via Unsplash, free license
The good news is that an experimental drug under development in the Marks lab was able to reduce both the calcium leak in the brain and neurocognitive symptoms in mice.
Marks and his team hope that a clinical trial is soon-to-come, as there is currently no treatment for this common and distressing impairment.
“As a clinician, one of the things I ask my patients with cancer is ‘What is the thing that affects you most in daily life?’ They say either brain fog or weakness, and those are things that a busy clinician typically doesn't have time to address,” says Guise. “It's a very important clinical problem with a huge unmet clinical need.”
The study also adds to the evidence that the calcium leak has an important role in cognitive deficits in general. “I think it's a powerful story that we’ve converged on a similar pathway that affects cognition in multiple disorders and multiple settings,” Marks says.
Explainer: What is chemobrain?
“Chemobrain,” sometimes called “chemo fog” or “chemo brain,” describes cognitive changes and memory problems that some cancer patients experience during or after chemotherapy.
It's a side effect of cancer treatments, including chemotherapy, radiation therapy, and sometimes hormone therapy. Chemobrain can manifest as difficulties with memory, concentration, and clear thinking.
The exact cause of chemobrain is not entirely understood. It is believed to result from the impact of cancer treatments on healthy brain cells, leading to disruptions in cognitive function. Symptoms can range from mild to more severe, depending on individual factors.
Some common signs of chemobrain include forgetfulness, difficulty concentrating, mental fogginess, and slower thinking.
Not all cancer patients experience chemobrain, and for those who do, the symptoms are often temporary. In many cases, cognitive function gradually improves after cancer treatment is completed. However, some individuals may continue to experience cognitive challenges for an extended period.
Management strategies for chemobrain include cognitive rehabilitation, mental exercises, and lifestyle modifications to support brain health.
Source: Columbia University