Preliminary differences in peripheral immune markers and brain metabolites between fatigued and non-fatigued breast cancer survivors: a pilot study
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Persistent cancer-related fatigue (PCRF) is one of the most troubling side-effects of breast cancer (BC) treatment. One explanatory model for PCRF is sickness behavior, which is a set of adaptive responses including sleepiness and depressed mood in reaction to an inflammatory trigger. Prior research has investigated differences in inflammatory cytokines between fatigued and non-fatigued BC survivors, but no study has examined differences in brain metabolites. Differences in inflammatory markers, and brain metabolites using proton magnetic resonance spectroscopy were evaluated within 16 fatigued and 13 non-fatigued BC survivors. Fatigued BC survivors had significantly higher ratios of two markers derived from brain metabolites; namely (a) creatine, normalized to total creatine (creatine + phosphocreatine (Cr/tCr)) ratio (P = 0.03) and (b) glutamate + glutamine (Glx) to N-acetyl-aspartate (NAA) ratio (P = 0.01) in the posterior insula compared to non-fatigued breast cancer survivor. Further, serum IL-6 was increased in fatigued women compared to non-fatigued women (P = 0.03), Using receiver operator curves (ROC) we determined that the posterior insula Glx/NAA ratio was the best predictor of fatigue with an overall area under the receiver operating characteristic curve (AUROC) of 79 %, with a sensitivity of 81 % and a specificity of 69 %. However, posterior insula Glx/NAA, Cr/tCr and serum IL-6 were not significantly correlated with one another implying the possibility of independent biological mechanisms for PCRF rather than an interrelated mechanism as represented by the sickness behavior model. This study provides novel preliminary evidence of several distinct neurobiological changes in the posterior insula associated with PCRF in BC survivors. Future, longitudinal studies are needed to explore these distinct biological phenomena where changes through time in peripheral immune markers and brain metabolites are examined to determine if they correlate with changes in fatigue.
KeywordsMagnetic resonance spectroscopy Persistent fatigue Breast cancer survivors Creatine Glutamate Cytokines C-reactive protein Posterior insula Anterior insula Anterior cingulate Occipital cortex
This research was supported by grants from the Ronald P. and Joan M. Nordgren Cancer Research Fund and the University of Michigan National Institutes of Health Clinical and Translational Awards (CTSA) grant number UL1RR024986.
Conflict of interest
The authors declare that they have no conflict of interest.
The experiments described in this manuscript comply with the current laws of the country in which they were performed.
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