Chemobrain: The Impact of Chemotherapy on Cognition

Cognition may be affected by chemotherapy. Research shows why.

Posted Jan 23, 2019

When we hear the word chemotherapy, we automatically think of cancer patients, and its destructive effects on them, though it is supposed to be a cure. Chemotherapy really means the use of drugs to treat any kind of disease, not only cancer. But it has become exclusively associated to cancer in the popular language.

Available chemotherapy for the treatment of different types of cancer is known to also have side effects that takes a toll on patient’s quality of life—fatigue, hair loss, vomiting, infections, anemia, and changes in mood and weight. More than half of chemotherapy patients develop also some sort of cognitive impairment.

What does chemotherapy do to the brain?

The cognitive impairment associated to chemotherapy is commonly known as chemobrain. Patients report to have increased memory lapses, trouble concentrating or remembering details and common things, or finding themselves taking longer to do mundane tasks that were not difficult before.

Many drugs are used as chemotherapy, and the use of a specific drug has to do with the type of cancer, its stage, the patient’s medical history, and other factors that may help determine which drug will have the best outcome and the least damaging side effects.

Larry Ostby, photo released by National Cancer Instiute, an agency part of the National Institutes of Health.
Cisplatin crystals.
Source: Larry Ostby, photo released by National Cancer Instiute, an agency part of the National Institutes of Health.

Among some of the most commonly used chemotherapeutic drugs we can find carmustine and cisplatin. These drugs target DNA, and prevent cells from dividing. However, this effect is not specific to cancer cells, and it can also affect other cells in the body that rapidly divide, such as those that make up our blood. Lung, breast, ovary, and other cancers are treated with this type of chemotherapy, which belong to the group of chemotherapeutic drugs called alkylating agents

Cytarabine is an antimetabolite, another chemotherapeutic drug that has been successfully applied to destroy cancer cells in leukemia patients, and also in the context of breast and lung cancers, among others.

However, carmustine, cisplatin and cytarabine are also to blame for chemobrain.

In 2006, a group of researchers based in Rochester, New York, showed that oligodendrocytes, a glial cell type found in the central nervous system of mammals, were especially sensitive to chemotherapy, as well as their precursor cells. They saw that in mice these drugs caused a decreased division of oligodendrocytes and increase in their death in the dentate gyrus and hippocampus, two brain regions associated with learning and memory.

Researchers from Stanford University and NYU found that another commonly used chemotherapeutic drug, methotrexate, has also effects on the oligodendrocyte precursor cells. They just published their results a few days ago (on January 10) where they analyzed the post-mortem tissue of young children and adults who underwent chemotherapy with methotrexate and saw the same effect on oligodendrocyte precursor cells that were described back in 2006.

The cognitive defects associated to the use of all the aforementioned chemotherapeutic drugs were long term, even after chemotherapy was no longer applied.

Why are Oligodendrocytes important in cognition?

Oligodendrocytes are in charge of providing the myelin sheath that envelopes the axons of neurons. Myelin ensures a proper transmission of the electrical signal along the axon, to reach the next neuron.

OpenStax under CC 4.0
Oligodendrocytes are enveloping the neuronal axon with myelin to promote rapid and efficient transmission of the nervous signal.
Source: OpenStax under CC 4.0

Defects in the noble task of oligodendrocytes in producing and coordinating the proper myelination of neurons cause important deficits in learning, motor skills, and cognition. Hence the importance of keeping one's population of oligodendrocytes healthy and constant throughout life. Decrease in myelination (demyelination), or alterations in the myelin sheath are hallmarks of other diseases such as multiple sclerosis.

Chemotherapeutic drugs seem to have a preference for oligodendrocytes and its precursor cells, which causes defects in myelination and therefore, cognition and behavior, giving rise to the chemobrain.

Can we stop Chemobrain?

So what can we do? Chemotherapy is currently the way to go to treat, palliate and control many different types of cancer, so it doesn’t seem feasible to stop the treatment in order to avoid chemobrain. But research on chemobrain might be able to bring solutions to the table, and hopefully, prevent one of the dreadful side effects of chemotherapy.

In the most recent research, microglia, another member of the glial cell population, was found to be the culprit of modulating the detrimental effects of methotrexate on oligodendrocyte precursors. Reducing microglia in the mouse brain showed a significant improvement from chemobrain. Giving the mice a special chow containing a drug that inhibits microglia survival was enough to protect the brain from the cognitive decline that methotrexate causes.

We need to understand exactly what’s going on in the chemobrain, and how all the different glial cell types (microglia, oligodendrocytes and astrocytes, which are also involved) interact with each other causing the cognition impairments after chemotherapy. Chemobrain is a lesser known side effect of chemotherapy and yet, one that can caused important distress on the patient and the cancer survivor. Research like this moves forward to ameliorate side effects, and whatever can improve the patients’ and survivors’ quality of life is a priority—because dealing with the cancer itself is more than enough.

To learn more about chemotherapy and its side effects, visit the National Cancer Institute.

References

Erin M. Gibson, Surya Nagaraja, Alfonso Ocampo, Lydia T. Tam, Lauren S. Wood, Praveen N. Pallegar, Jacob J. Greene, Anna C. Geraghty, Andrea K. Goldstein, Lijun Ni, Pamelyn J. Woo, Ben A. Barres, Shane Liddelow, Hannes Vogel, Michelle Monje. Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment. Cell, Volume 176, Issues 1–2, 10 January 2019

David H. Gutmann, Clearing the Fog surrounding Chemobrain, Cell, Volume 176, Issues 1–2, Pages 2-4, 10 January 2019.

Joerg Dietrich, Ruolan Han, Yin Yang, Margot Mayer-Pröschel, Mark Noble CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. Journal of Biology 5:22, 30 November 2006.

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