Candidate mechanisms for chemotherapy-induced cognitive changes

Abstract

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.