Chemotherapy for breast cancer can cause reduced cognitive functioning ("chemo brain" or "chemobrain"). Chemo brain is characterized by reduced verbal ability, impaired decision making, faulty short-term memory and other deficits. Chemo brain is the result of brain damage, much of which heals over time and some of which appears to persist for decades. However, chemo brain does not appear to set the stage for Alzheimer's disease in old age. While there are no specific treatments for chemo brain, breast cancer survivors can adopt coping strategies to address its symptoms.
Symptoms of chemo brain
At least one-third of women undergoing chemotherapy for breast cancer experience chemo brain during treatment and for some time afterwards. Studies using standard psychological testing have reported that chemotherapy reduces verbal ability, slows cognitive processing speed, impairs executive functioning, and reduces psychomotor processing speed. Cognitive processing speed refers to the ability to automatically and fluently perform relatively easy or routine cognitive tasks, especially when high mental efficiency (i.e., attention and focused concentration) is required. Executive functioning refers to the ability to organize thoughts and prioritize tasks, manage time well, make plans, and adapt to changing situations. Psychomotor processing speed refers to reaction time when a physical task is involved. It involves the coordination of a sensory or cognitive process and a motor activity.
The symptoms of chemo brain include slowed thinking and decision making, trouble remembering or spelling common words, problems with short-term memory and concentration, and reduced ability to multitask. There are glitches in the brain's operations. Unconscious mistakes can occur in tasks that are simple and routine. Typing and spelling errors may become common and all written work has to be checked for errors. Chemo brain can feel like moving through a fog, where the outlines of thoughts are indistinct and it's difficult for ideas to fully form. Conscious thinking itself can become more difficult, so that it takes effort to complete a thought or come to a conclusion.
Chemo brain is caused by brain injury
Researchers initially assumed that chemo brain did not involve actual physiological brain damage, in part because it was thought that chemotherapy did not cross the blood-brain barrier. Instead, the cognitive symptoms reported by women were studied as though they were primarily a consequence of depression or other emotional responses to breast cancer diagnosis and treatment. However, it has now been established that chemotherapy drugs can cause measurable brain damage in breast cancer patients.
Breast cancer patients who have undergone chemotherapy have been shown to have reduced (1) activation in the left middle dorsolateral prefrontal cortex and premotor cortex; (2) left caudal lateral prefrontal cortex activation; (3) hippocampus size; and (4) white matter integrity compared to controls.
Studies that have compared women's brains before and after chemotherapy have reported (1) reduced left caudal lateral prefrontal cortex activation; (2) injury to white matter (likely reflecting a combination of axonal degeneration and demyelination); and (3) reduced gray matter density in bilateral frontal, temporal, and cerebellar regions and right thalamus.
A study of mice who were treated with CMF (methotrexate, cyclophosphamide, and 5-fluorouracil) chemotherapy demonstrated that methotrexate disrupted the formation of new nerve cells in the brain. Another study reported that rats treated with Adriamycin (doxorubicin) experienced significant declines in functional connectivity between the bilateral primary visual cortex and the right forelimb somatosensory cortex, and the right and left superior colliculus.
How long does chemo brain last?
Chemo brain normally starts to improve within one year of treatment, but some of the brain damage appears to be permanent. As mentioned above, chemotherapy can disrupt the formation of new nerve cells (neurogenesis) in the brain. Neurogenesis occurs throughout adulthood and is controlled by cell cycle regulators. The hippocampus, a brain region important to memory and learning, is a primary site of neurogenesis. Chemotherapy drugs that act by inhibiting cell cycle progression appear to produce cognitive impairment by disrupting neurogenesis in the hippocampus. This means that neurogenesis can start to repair some of the damage caused by chemotherapy once treatment ends. The perception of being in a fog lifts and problems with short-term memory and executive functioning appear to resolve within one to five years of the end of treatment. However, problems with verbal fluency and psychomotor processing speed can persist long afterwards.
Long-term effects of chemotherapy on cognitive functioning
Recently, a Dutch study investigated whether cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for breast cancer is associated with continued cognitive performance deficits more than two decades after treatment. This is the first study to examine long-term effects of chemotherapy on cognitive performance (see Neuropsychological Performance in Survivors of Breast Cancer More Than 20 Years After Adjuvant Chemotherapy below). CMF was the standard breast cancer chemotherapy from the 1970s to the 1990s. The study included 196 women with breast cancer who had been treated with CMF chemotherapy between 1976 and 1995 and a control sample of women never diagnosed with cancer. The average time since treatment was 21 years. Neuropsychological tests were used to compare the two groups. Women who had been treated with endocrine therapy (tamoxifen or aromatase inhibitor) or who had experienced a breast cancer recurrence were excluded from the study. Results were adjusted for age, level of education, and depression.
The women who received CMF chemotherapy were found to perform worse on cognitive tests than matched controls. The differences in performance were subtle and occurred primarily in word learning, memory and information processing speed. The breast cancer survivors also had lower scores on psychomotor speed (coordination of thinking and hand movement). The magnitude of the effects was comparable to approximately six years of age-related decline in cognitive function, according to the authors.
Risk factors for chemo brain
Not all women experience chemo brain, however predicting which women would be most susceptible is not possible. There is some evidence that old age, low cognitive reserve and depression each are associated with increased magnitude of the cognitive deficits associated with chemotherapy. Cognitive reserve refers to the difference between the cognitive performance predicted by an individual's level of brain pathology or injury and that individual's actual performance. In other words, those whose measured cognitive performance is better than predicted have high reserve, whereas those who perform worse than predicted have low reserve. This information does not appear to be particularly useful for determining who would be most susceptible to chemo brain.
Endocrine treatments can also impair cognitive functioning
Tamoxifen and aromatase inhibitors can also cause some of the symptoms of chemo brain in some women. However, this appears to be the result of brain estrogen deprivation, not outright brain damage. Therefore, patients who undergo chemotherapy followed by endocrine treatment might find that memory lapses, for example, persist long after chemotherapy has ended. The symptoms caused by estrogen deprivation appear to improve within a year after endocrine treatment ends. Women who undergo radiotherapy can also experience chemo brain-like symptoms. While the reasons for this have not been explained, these symptoms also appear to be temporary.
Does chemo brain lead to Alzheimer's disease?
Although the evidence is mixed, chemo brain does not appear to lead to Alzheimer's disease in old age. Several studies have examined the question as to whether breast cancer patients who undergo chemotherapy have a higher risk of developing dementia in old age:
- A large prospective study that included 62,565 U.S. breast cancer patients who were at least 65 and free of cognitive impairments at diagnosis reported that the risk of developing Alzheimer disease, vascular dementia, or other dementias was lower in patients who received chemotherapy for breast cancer.
- Another study of older U.S. breast cancer survivors (2,913 of whom received chemotherapy and 18,449 who did not) reported that chemotherapy was not associated with a greater risk of the development of dementia over time for any of three age groups: 66 to 70, 71 to 75, or 76 to 80.
- A study that included 18,360 older women diagnosed with Stage II, III, or IV breast cancer found that there were significant differences at baseline between individuals who received and did not receive chemotherapy. In the first few years after breast cancer diagnosis, dementia was more common in women who had not had chemotherapy, probably reflecting group differences at baseline. In the longer term, diagnoses of dementia were more common in women who had chemotherapy treatment.
Strategies for coping with chemo brain
There are no proven drug treatments for chemo brain. Regular exercise and other physical activity have been shown to improve executive function, information processing speed and concentration in women with chemo brain. Cognitive and memory training have been shown to improve cognitive function, memory, verbal functioning and orientation/attention, although studies are inconsistent.
Breast cancer patients can also adopt coping strategies designed to address specific chemo brain symptoms. First, it might be helpful to know that while chemo brain is unpleasant, it does not affect all areas of intelligence and it is to a great degree temporary. To address specific chemo brain symptoms, women can make lists and keep detailed calendars to organize their lives, become more systematic in their daily routines, check all their work or other written output, and prepare more thoroughly for business meetings or travel. In other words, women can take advantage of the more lucid times to organize and set up for the times when thinking is more difficult and less reliable.
Getting enough sleep (to facilitate the brain's memory storage and housekeeping functions) could be important. Turmeric has been shown to protect the brain from various types of injury and could possibly reduce the magnitude of chemo brain. It might also be helpful to avoid the factors listed in section below that are known to contribute to cognitive impairment in old age.
Preserving brain health in old age
Generally speaking, rates of cognitive impairment increase with age. However, individuals vary considerably and genetic heritage is only part of the reason. The following factors increase the likelihood of cognitive impairment in old age: depression; lack of exercise; diet high in saturated fat, trans fats and/or sugar; high levels of systemic inflammation; diabetes; high blood pressure; and high cholesterol. Maintaining satisfying social connections and a healthy lifestyle might protect against cognitive decline in some women.
Please see our article on the side effects of chemotherapy for more information on the long-term after effects of chemotherapy. Below are links to recent studies on chemo brain. For a more complete list of studies, please click on chemo brain.