The etiology of cognitive impairment after chemotherapy remains unknown although a number of mechanisms have been postulated. Candidate mechanisms include: direct neurotoxic effects (e.g. injury to neurons or surrounding cells, altered neurotransmitter levels); oxidative stress and DNA damage; induced hormonal changes; immune dysregulation and/or release of cytokines; and blood clotting in small CNS vessels. Some patients may have a genetic predisposition to develop cognitive impairment.
Several studies have examined changes in brain morphology and activation patterns associated with chemotherapy utilizing both structural and functional imaging techniques. Studies using magnetic resonance imaging (MRI) have reported reduced volume of brain structures important for executive functioning (e.g., frontal cortex) and changes in the integrity of white matter tracts in patients treated with chemotherapy. However, one study that examined hippocampal volume found no volumetric differences when comparing breast cancer patients treated with chemotherapy with those not treated with chemotherapy. Early results from a functional MRI study revealed a pattern of reduced activation in frontal cortex during a working memory task in patients treated with chemotherapy compared with patients not treated with chemotherapy and healthy controls. A study using Oxygen-15 positron emission tomography (PET) demonstrated that breast cancer patients treated with chemotherapy, when compared to breast cancer patients who received no chemotherapy and healthy controls, showed decreased metabolic activity in the prefrontal cortex during short- and long-term memory tasks. Evidence for compensatory activation of brain structures not typically utilized for a given cognitive task has also been reported, raising the possibility that performance on neuropsychological testing may remain in the normal range through altered activation brain patterns. Electrophysiologic studies examining the P-300 event-related brain potential reported decreases in amplitude (intensity of neural activation) and latency (timing and duration of activation) of P-300 associated with chemotherapy, which is consistent with changes in information processing capacity. Taken together, these data suggest that chemotherapy is associated with changes in brain structure and function.
Research examining the impact of chemotherapy on learning and memory in animal models is emerging. Studies have demonstrated that commonly used chemotherapy agents, administered peripherally, can cause disruption of learning and memory across a variety of tasks in both mouse and rat models. In contrast, one study did not find any detrimental effects of treatment with 5-fluorouracil on rat behavior. Studies utilizing histological analyses of the brain of animals that received chemotherapy have demonstrated cell death and slowing of cell division in structures critical for memory and learning, including the subventricular zone, the dentate gyrus of the hippocampus, and the corpus callosum.
One potential mechanism leading to cognitive dysfunction (and fatigue) is the stimulation of neurotoxic cytokines by cancer and chemotherapy. Treatments that stimulate cytokine production (e.g., interferon) have been associated with a variety of symptoms, including cognitive deficits. Further, patients with hematological malignancies were found to have elevated levels of interleukin-1 (IL-1), IL-1 receptor agonist (IL1-RA), IL-6, IL-8, and TNF-alpha compared to normative values prior to treatment and higher levels of IL-6 were associated with poorer performance on measures of executive function before treatment. Preliminary data indicate that multiple cytokines are elevated in subjects who have been treated for colorectal and breast cancer, in the absence of recurrence of disease, but that the levels were not higher in subjects who had received chemotherapy. There is emerging evidence that cytokine levels might relate to deficits in cognitive function.
Genetic polymorphisms may increase risk for chemotherapy-induced cognitive changes. One study has reported an association between the E4 allele of apolipoprotein E (associated with risk for Alzheimer’s disease and poorer cognitive outcomes following insults to the brain) and poorer cognitive performance in long-term survivors of breast cancer and lymphoma. Additional genetic polymorphisms related to efficiency of the blood brain barrier (e.g., differential expression of MDR-1) and the functioning of cytokines (e.g., polymorphisms of IL-6), neurotransmitters (e.g., COMT) and DNA repair mechanisms (e.g., XRCC1) might also be important.