Brain-derived neurotrophic factor polymorphism Val66Met protects against cancer-related fatigue.

Cancer-related fatigue is an extremely common and debilitating psychiatric symptom that affects up to 80% of cancer patients. Despite its negative impact on the patient's quality of life, there is no well-established biomarker or mechanisms associated with this debilitating condition. The functional brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with a variety of psychiatric illnesses. We hypothesized that Val66Met may influence the risk for developing cancer-related fatigue. BDNF Val66Met was analyzed by polymerase chain reaction in 180 patients with confirmed cancer diagnoses. Fatigue was measured using the Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) questionnaire. Depression was measured using the Hamilton Depression Scale (HAM-D). Data were transformed when necessary and regression models were constructed to access the association between genotype and symptom severity. Participants carrying the Met allele reported significantly less fatigue compared to the Val/Val genotype group. The presence of the Met allele did not influence depression levels. The results suggest that the BDNF Val66Met polymorphism confers protective advantage against cancer-related fatigue; whereas having the Val/Val genotype may be a genetic risk factor. Findings from this study not only provide clues to the neural basis of cancer-related fatigue, but also allow for symptom severity prediction and patient education with the goal to improve symptom management.

Induction of fatigue-like behavior by pelvic irradiation of male mice alters cognitive behaviors and BDNF expression.

Fatigue and cognitive deficits are often co-occurring symptoms reported by patients after radiation therapy for prostate cancer. In this study, we induced fatigue-like behavior in mice using targeted pelvic irradiation to mimic the clinical treatment regimen and assess cognitive behavioral changes. We observed that pelvic irradiation produced a robust fatigue phenotype, a reduced rate of spontaneous alternation in a Y-maze test, and no behavioral change in an open field test. We found that reversal learning for fatigued mice was slower with respect to time, but not with respect to effort put into the test, suggesting that fatigue may impact the ability or motivation to work at a cognitive task without impairing cognitive capabilities. In addition, we found that mice undergoing pelvic irradiation show lower whole-brain levels of mature BDNF, and that whole-brain proBDNF levels also correlate with spontaneous alternation in a Y-maze test. These results suggest that changes in BDNF levels could be both a cause and an effect of fatigue-related changes in behavior.

[Corrigendum] Cancer­related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction.

Following the publication of the article, the authors realized that they have overlooked acknowledging the assistance they received from the Murine Phenotyping Core at NHLBI. Therefore, the Acknowledgements section of the Declarations should also have stated the following: 'We would like to thank the Murine Phenotyping Core at NHLBI for all their help with the mouse experiments, including Dr Danielle Springer, Audrey Noguchi, Michele Allen, Heather Potts and Morteza Peiravi.' The authors regret their oversight in failing to include this information in the Acknowledgements section of their paper. [the original article was published in International Journal of Molecular Medicine 45: 485­496, 2020; DOI: 10.3892/ijmm.2019.4435].

Cancer­related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction.

Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non­metastatic prostate cancer (NMPC). Despite the efficacy, treatment­related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. A total of 64 participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy­Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants' whole blood. An ADT/RT­induced fatigue mouse model was developed, with fatigue measured as a reduction in voluntary wheel­running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using western blot analysis of glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). The results demonstrated that fatigue in the ADT group was exacerbated during RT compared with the non­ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non­fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated the synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. In conclusion, these findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model and its mechanism may be related to bioenergetics in the CNS.