The effect of systemic chemotherapy on neurogenesis, plasticity and memory

Chemotherapy has been enormously successful in treating many forms of cancer and improving patient survival rates. With the increasing numbers of survivors, a number of cognitive side effects have become apparent. These have been called "chemobrain" or "chemofog" among patient groups, who describe the symptoms as a decline in memory, concentration and executive functions. Changes which, although subtle, can cause significant distress among patients and prevent a return to the quality of life experienced before treatment. This cognitive side effect of chemotherapy was not anticipated as it had been assumed that chemotherapy agents, administered systematically, could not cross the blood-brain barrier and that the brain was therefore protected from their action. It is now realised that low concentrations of many chemotherapy agents cross the blood-brain barrier and even those that are completely prevented from doing so, can induce the production of inflammatory cytokines in peripheral tissues which in turn can cross the blood-brain barrier and impact on the brain. A large number of patient studies have shown that cognitive decline is found in a proportion of patients treated with a variety of chemotherapy agents for different types of cancer. The deficits experienced by these patients can last for up to several years and have a deleterious effect on educational attainment and ability to return to work. Imaging studies of patients after systemic chemotherapy show that this treatment produces structural and functional changes in the brain some of which seem to persist even when the cognitive deficits have ceased. This suggests that, with time, brain plasticity may be able to compensate for the deleterious effects of chemotherapy treatment. A number of mechanisms have been suggested for the changes in brain structure and function found after chemotherapy. These include both central and peripheral inflammatory changes, demyelination of white matter tracts, a reduction in stem cell proliferation in both the hippocampal neurogenic region and by oligodendrocyte precursors as well as changes in hormonal or growth factor levels. A number of possible treatments have been suggested which range from pharmacological interventions to cognitive behavioural therapies. Some of these have only been tested in animal models while others have produced varying degrees of improvement in patient populations. Currently, there is no recognised treatment and a greater understanding of the causes of the cognitive decline experienced after chemotherapy will be key to finding ways of preventing or treating the effects of chemobrain.