Memory problems and other cognitive disorders after chemotherapy

Published: 01-11-2020

Last modified: 21-09-2021

Cancer patients receiving chemotherapy often experience problems with memory, attention, and other cognitive disorders. These dysfunctions are called “chemobrain” and they often hinder work or study and reduce quality of life. What is the cause of them?

Research shows that cognitive disorders occur in a dozen or even about 70% of people treated with chemotherapy. Patients report problems with attention and concentration, with memory, their language skills deteriorate, they have difficulty carrying out several tasks simultaneously and become disorganized. The subjective feeling of symptoms does not always go hand in hand with the objective results of neuropsychological tests, which also makes it difficult to determine the frequency of chemobrain. Disorders of this type were diagnosed mainly in patients with breast cancer, but also in in people with lung cancer, cancers of the head and neck, testicular cancer, and lymphomas. After the end of cancer treatment, it may take several months to even several years to return to normal functioning.

The causes of chemobrain – cytokines

The exact reasons for the occurrence of cognitive disorders after chemotherapy are not known, but the most important are cytokines. These proteins are responsible for the functioning of nerve and glial cells and regulate the levels of neurotransmitters such as dopamine and serotonin, which are essential for cognitive function.

Many studies have shown that chemotherapy increases the levels of cytokines such as TNF-α, IL-6, IL-8, IL-10 and MCP-1, and these changes are greater in patients who experience cognitive impairment. The elevated level of the pro-inflammatory cytokine IL-6 observed in patients treated for breast cancer correlates with decreased cognitive functioning. Patients who receive immunotherapy consisting of interleukin-2 or interferon-alpha often have symptoms such as reduced information processing speed, deterioration of spatial abilities and other cognitive processes. Animal studies have shown that after administration of a drug that increases TNF-α levels, elevated levels of this cytokine are present in the hippocampus (the structure responsible for memory) and the cerebral cortex (responsible for complex thought processes).

957/5000Despite many studies that show a correlation between the level of cytokines and deterioration in functioning, it is still unknown what mechanism causes cytokines to deteriorate memory, concentration and other symptoms.

Chemotherapy drugs do not cross the blood-brain barrier, so they are unlikely to directly increase cytokine levels in the brain. Rather, it occurs through circulating cytokines that affect the levels of these proteins in the brain. It is also unclear what happens after the increase in cytokine levels in the brain. One hypothesis is that cytokines lead to changes in the neurotransmitter system, such as glutamate, serotonin, dopamine, noradrenaline, GABA, acetylcholine. They can also affect neuropeptides and nerve growth factors. Another possible mechanism is an increase in the level of free radicals (e.g., nitric oxide), which increase oxidative stress and damage DNA in nerve cells.

The causes of chemobrain – hormones

The term “chemobrain” can be confusing because it is not induced only by chemotherapy. Cognitive disorders also occur in patients treated with hormone therapy, which is used, among others, in patients with breast or prostate cancer.

Estrogen and testosterone play a neuroprotective role, therefore drugs that lower the level of these hormones lead to a deterioration in cognitive functioning.

Individual predisposition to chemobrain

Some patients are at greater risk of developing cognitive impairment, others are less at risk. People with lower baseline cognitive functioning, such as the elderly or those with low education, are more vulnerable.

Genetic predisposition is also important. People with the E4 allele of apoliprotein E (the same one that increases the risk of Alzheimer’s disease) are more likely to suffer from cognitive decline as a result of cancer treatment. Other genes that may be of importance are the gene encoding BDNF (brain derived neurotrophic factor) and the gene encoding COMT (catechol-O-methyltransferase). BDNF is involved in the repair functions of neurons, while COMT regulates the level of catecholamines, including dopamine.

Cognitive impairment can also be caused by the stress that accompanies cancer and its treatment. Stress, depression or fatigue can directly affect the feeling of functional deterioration, but it also happens indirectly, by increasing the level of cytokines, caused by stress.

References:

1. Bury M. (2015). Uwarunkowania zaburzeń poznawczych powstających wskutek leczenia onkologicznego i wybrane sposoby terapii kognitywnej. Psychiatria i Psychologia Kliniczna, 15(1), 26-32. (pdf na icm.edu.pl)
2. Kok-Ho H. (2015). Insights into the mechanism of ‘chemobrain’: deriving a multi-factorial model of pathogenesis. Australian Medical Student Journal, 6(1), 23-27. (pdf na amsj.org)
3. Wang X., Walitt B., Saligan L., Tiwari A., Cheung C., Zhang Z. (2015). Chemobrain: A critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine 72, 86-96. (pdf na researchgate.net)

Author: Maja Kochanowska