Cognitive complications of cancer and cancer-related treatments – Novel paradigms

Abstract

As advances in diagnostics and therapeutic strategies in oncology have increased the number of cancer survivors, the investigation of the mechanisms associated with long-term cognitive complications of cancer treatment has become an important topic of interest. The neurotoxic effects of chemotherapeutic agents have been described in pre-clinical and clinical research. In vitro and rodent studies have identified some underlying mechanisms contributing to chemotherapy-induced neurotoxicity and cognitive impairment for various chemotherapy drugs and other cancer treatments. However, investigation of the direct biological effects of cancer and other potential contributing factors in the pathogenesis of cancer-related cognitive impairment (CRCI) has only recently come into focus. This review will highlight evidence from pre-clinical tumor-bearing rodent models suggesting that cancer influences the cognitive and behavioral changes reported in human cancer populations through direct or indirect pathways that alter the normal neuroinflammatory responses, induce structural brain deficits, and decrease neurogenesis. We reflect on human clinical cancer research indicating that cognitive and behavioral changes precede cancer treatment in some malignancies. We also highlight implications for future areas of CRCI research based on novel findings on the interplay between cancer, chemotherapy, inflammation, tau pathology, and dysregulation of the microbiota-gutbrain axis.

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

“…Clearly, there cannot be a direct connection between neurodegeneration and UV light exposure: sun UV ra-diation cannot penetrate the skull. At the same time, we know that the blood-brain barrier (BBB) protects the central nervous system from many exogenous substances, even though part of chemical compounds, probably at lower concentrations, can normally pass the BBB [71] Chemotherapy agents (such as cisplatin) could pass through the BBB and cause chemotherapy-related cognitive impairment because of hippocampal synaptic damage and neural cell loss [72,73]. Moreover, the BBB structure and functioning is also reduced with age [71,74].…”

Oxidative Stress and Cognitive Alterations Induced by Cancer Chemotherapy Drugs: A Scoping Review

“…Compared to in vivo studies, relatively few in vitro studies have investigated the direct effects of anticancer drugs on neurons [38][39][40]. In primary cultures of rat neural stem cells or progenitor cells and hippocampal neurons, cisplatin and temozolomide induced mitochondrial DNA damage, impaired respiratory activity, and increased oxidative stress [39,40].…”

“…Compared to in vivo studies, relatively few in vitro studies have investigated the direct effects of anticancer drugs on neurons [38][39][40]. In primary cultures of rat neural stem cells or progenitor cells and hippocampal neurons, cisplatin and temozolomide induced mitochondrial DNA damage, impaired respiratory activity, and increased oxidative stress [39,40]. However, the presence of antioxidants in the culture medium used in cell culture experiments may be sufficient to block the effect of anticancer drugs and therefore, these systems are not suitable for examining ROS-mediated neurotoxicity because they may not reflect the actual conditions of chemotherapy-treated animal models or patients.…”

Impact of Adjunct Testosterone on Cancer-Related Fatigue: An Ancillary Analysis from a Controlled Randomized Trial

“…Possible factors mediating CRCI include activation of microglia, which may block neurogenesis or alter neural impulse time [ 97 ], hippocampal shrinkage caused by glucocorticoids [ 38 , 39 ], and effects from chemotherapy such as hippocampal oxidative damage [ 85 ] and neuroinflammation, which is linked to cognitive impairment due to alterations in myelin structure and myelination [ 98 ]. The absence of standardized assessments for CRCI [ 99 ] and limited association between patient-perceived cognitive changes and neurocognitive test results [ 100 ] make it difficult to identify, measure, and track CRCI in cancer patients.…”