Evidence for chemotherapy-induced cognitive changes comes from studies that have used neuropsychological testing, imaging (structural and functional magnetic resonance imaging (MRI) and positron emission tomography (PET)) and electrophysiological (electroencephalogram) assessments. Emerging data from animal studies also support the effect of chemotherapy on cognitive function.
Most chemotherapy agents administered systemically do not cross the blood–brain barrier in significant doses; however, the amount that enters the brain can be modified by genetic variability in blood–brain barrier transporters. In addition, recent data from animal studies suggest that very small doses of common chemotherapy agents can cause cell death and reduced cell division in brain structures crucial for cognition, even at doses that do not effectively kill tumour cells.
Chemotherapy might cause cognitive changes through DNA damage caused directly by the cytotoxic agents or through increases in oxidative stress. Many chemotherapeutic agents also cause the shortening of telomeres, thereby accelerating cell ageing. Genetic variability in DNA-repair genes might influence the extent of, and recovery from, chemotherapy-associated DNA damage.
Chemotherapy-induced cognitive changes might also be related to the neurotoxic effects of cytokine deregulation. Cytokine deregulation and inflammation can also lead to increased oxidative stress, which could establish a cycle of increased DNA damage that triggers additional cytokine release.
Variability in genes that regulate neural repair and/or plasticity, such as apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF), and neurotransmission, such as catechol-O-methyltransferase (COMT), might increase the vulnerability of an individual to chemotherapy-induced cognitive changes.
Changes in levels of oestrogen and testosterone are associated with cognitive decline, and can be influenced by chemotherapy (for example, chemotherapy-induced menopause) or hormonal treatments, such as tamoxifen or aromatase inhibitors for breast cancer or androgen ablation for prostate cancer.
The effects of chemotherapy-associated cardiovascular toxicity and alterations in neuroendocrine function on cognitive function require investigation.
The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatment-induced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/or have independent effects on cognitive function.
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The authors are supported by grants from the Office of Cancer Survivorship of the US National Cancer Institute and a National Institutes of Health Roadmap U54 Grant.
The authors declare no competing financial interests.
- Magnetic resonance imaging
A noninvasive technique that produces high-resolution, computerized images of internal body tissues. Structural MRI enables abnormalities of brain structure to be evaluated and volumetric measurements of specific structures to be made. Functional MRI enables activation patterns in various brain areas in response to the performance of cognitive or motor tasks to be examined.
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Physiological response to infection that includes symptoms such as decreased activity level, fatigue, decreased motivation and cognitive problems.
- Vagus nerve
The vagus nerve is the only cranial nerve that extends from the brainstem to all the organs in the abdomen.
The process by which neurons are damaged or killed through the over-activation of receptors for the excitatory neurotransmitter glutamate.
- Long-term potentiation
Long-lasting increase in the functioning of a synapse, which is thought to be related to neural plasticity and the cellular basis for learning and memory.
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Ahles, T., Saykin, A. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7, 192–201 (2007). https://doi.org/10.1038/nrc2073
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