Emerging mechanistic underpinnings and therapeutic targets for chemotherapy-related cognitive impairment

Abstract

Purpose of review: Modern innovations in cancer therapy have dramatically increased the number of cancer survivors. An unfortunately frequent side-effect of cancer treatment is enduring neurological impairment. Persistent deficits in attention, concentration, memory, and speed of information processing afflict a substantial fraction of cancer survivors following completion of these life-saving therapies. Here, we highlight chemotherapy-related cognitive impairment (CRCI) and discuss the current understanding of mechanisms underlying CRCI.

Recent findings: New studies emphasize the deleterious impact of chemotherapeutic agents on glial-glial and neuron-glial interactions that shape the form, function and plasticity of the central nervous system. An emerging theme in cancer therapy-related cognitive impairment is therapy-induced microglial activation and consequent dysfunction of both neural precursor cells and mature neural cell types. Recent work has highlighted the complexity of dysregulated intercellular interactions involving oligodendrocyte lineage cells, microglia, astrocytes, and neurons following exposure to traditional cancer therapies such as methotrexate. This new understanding of the mechanistic underpinnings of CRCI has elucidated potential therapeutic interventions, including colony-stimulating factor 1 receptor inhibition, TrkB agonism, and aerobic exercise.

Summary: Traditional cancer therapies induce lasting alterations to multiple neural cell types. Therapy-induced microglial activation is a critical component of the cause of CRCI, contributing to dysregulation of numerous processes of neural plasticity. Therapeutic targeting of microglial activation or the consequent dysregulation of neural plasticity mechanisms are emerging.

Figure 1:. Putative mechanisms underlying cancer therapy-induced cognitive disorder

Schematic illustration of core mechanisms mediating cancer therapy-induced cognitive impairment. While four distinct mechanisms (clockwise from top left: neurotransmission, BDNF signaling, oxidative stress, and neuroinflammation) have been identified as key modulators of the cognitive disorder associated with cancer therapy, many of these pathways share common regulatory mechanisms. Radiation and chemotherapy-induced reactive microglia (red cells) alter synaptic pruning and neurotransmission, BDNF signaling, and neuroinflammation via increased TNFα and IL6 levels centrally or peripherally by macrophages (green cells). This leads to subsequent impairment of oligodendrocyte precursor cell (OPC) proliferation and myelination by oligodendrocytes (blue cells) and neural precursor cell (NPC) proliferation and neurogenesis (orange cells). Radiation and chemotherapy also lead to increased reactive oxygen species (ROS) and TNFα signaling and consequent inhibition of neurogenesis and myelination via decrements in precursor cell proliferation. Many of these deficits can be rescued through aerobic exercise, including increases in glutamatergic, dopaminergic, serotonergic, and BDNF signaling.