Candidate mechanisms for chemotherapy-induced cognitive changes

Key Points

  • 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.

Abstract

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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Figure 1: Neuroimaging methods relevant to the assessment of cognitive changes.
Figure 2: Candidate mechanisms.

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Acknowledgements

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.

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Correspondence to Tim A. Ahles.

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Glossary

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.

P-300

The P-300 is a neural-evoked potential component of the EEG. The P-300 is an event-related potential that is triggered approximately 300 milliseconds after the presentation of an unexpected or novel stimulus.

Encephalopathy

Encephalopathy refers to alterations in brain structure and/or function that can have several causes, including infection, exposure to toxic chemicals (for example, chemotherapy), poor nutrition or lack of oxygen or blood flow to the brain. The primary symptoms of encephalopathy are alterations in mental status.

Leukoencephalopathy

Alterations of the white matter of the brain owing to infection or exposure to toxic chemicals.

Ototoxicity

Toxicity associated with organs or nerves involved with hearing or balance.

Cerebellar symptoms

The cerebellum is an area of the brain that is important for the integration of sensory input and motor output. Disorders of the cerebellum include symptoms associated with equilibrium, posture, motor learning and fine motor control.

Positron emission tomography

A nuclear medicine imaging technique that produces a three-dimensional image of functional or metabolic processes in the body by scanning for a radioactive isotope (for example, a radiolabelled chemotherapy agent) that has been injected into the bloodstream.

Ataxia telangiectasia

A disorder caused by a mutation of the ataxia telangiectasia mutated (ATM) gene, which is important for DNA repair. Ataxia telangiectasia causes progressive immunological and neurological problems, including cognitive symptoms, and people with ataxia telangiectasia have a significantly increased risk of cancer.

Xeroderma pigmentosum

A genetic DNA-repair disorder in which the body is unable to repair DNA damage or mutations caused by ultraviolet light.

Glia

A group of non-neuronal cells in the brain that provide support and nutrition, form myelin and influence signal transmission in the nervous system.

Sickness behaviour

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.

Excitotoxicity

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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