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Chemotherapy-induced gray matter abnormalities in cancer survivals: a voxel-wise neuroimaging meta-analysis.
Running Niu1, Mingying Du1, Lu Lu2, and Peng Zhou1

1Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China, 2Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Chengdu, China

Synopsis

The present meta-analysis investigated the grey matter abnormalities in non-CNS cancer survivals treated with chemotherapy using Anisotropic Effect Size Signed Differential Mapping (AES-SDM) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guides. Compared with controls, the non-CNS cancer survivals treated with chemotherapy exhibit widespread grey matter abnormalities in brain, especially in prefrontal-temporal pathway, which was significantly affected by the time length since chemotherapy. This pattern of grey matter volume changes might improve our understanding of the pathophysiological nature of chemotherapy related cognitive dysfunctions.

Background and Purpose

“Chemobrain” is the term used to describe the alterations of cognitive function reflecting the central nervous system (CNS) toxic effects of systemic chemotherapy [1]. Chemobrain symptoms significantly impact multiple activities of cancer survivors such as in maintaining work performance, social interaction, and carrying out daily tasks such as cooking and driving [2, 3]. Neuroimaging findings on brain grey matter volume (GMV) changes of chemobrain are not consistent. To our knowledge, no meta-analysis has been published to demonstrate brain GMV changes of chemobrain based on original coordinates. Thus we aimed to investigate the grey matter abnormalities in non-CNS cancer survivals treated with chemotherapy using Anisotropic Effect Size Signed Differential Mapping (AES-SDM) software.

METHODS:

We identified studies published up to Sep 2018 that compared grey matter in non-CNS cancer survivals treated with chemotherapy (CT+, 10 data sets including 433 individuals) and cancer survivals without chemotherapy (CT-, 7 data sets including 210 individuals) or healthy controls (HC, 7 data sets including 539 individuals) using whole-brain VBM (figure 1-2). All the process of this meta-analysis was according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guides. Two authors independently assessed the quality of the included studies using a 12¬≠point checklist. A jackknife sensitivity analysis and the heterogeneity analysis was conducted to insure the replicablity and robustness of the results. The possibility of publication bias for the brain regions with GMV alteration was examined by Egger’s test [4]. The potential effects of the mean age, percentage of female, time since chemotherapy of the cancer survivals treated with chemotherapy on GMV differences were examined by simple linear regression in AES-SDM.

RESULTS

Four hundred and thirty three cancer survivals treated with chemotherapy (CT+) (mean age 51.92 years), 210 cancer survivals without chemotherapy (CT-) (mean age 49.87 years) and 539 healthy controls (HC) (mean age 56.84 years) were included. The quality assess of our included studies showed that the quality score was between 9 -12 and analysis of heterogeneity did not detected significant statistical heterogeneity. Egger's tests were nonsignificant both in main meta-analysis and subgroup analysis. Compared with controls, the post-chemotherapy cancer survivals showed reduced GMV in left superior temporal gyrus (STG), right fusiform gyrus (FG), corpus callosum (CC) (right superior frontal gyrus, medial orbital, SFG.med.orb) and right medial (SFG.med) and dorsolateral superior frontal gyrus (SFG.dl) (Fig.3). The cancer survivals treated with chemotherapy showed reduced GMV in the right fusiform and right medial orbital (SFG.med.orb) and SFG.dl when compared to non- chemotherapy cancer survivals. The findings of subgroup analyses revealed different results between 1.5 T and 3.0 T MRI studies, especially the prefrontal cortex alterations (Figure 4). Meta regression analysis showed that the reduced grey matter volume in right dorsal lateral superior frontal gyrus was significantly related to the time since chemotherapy in cancer survivals.

DISCUSSION

The main findings revealed that three regions in prefrontal cortex demonstrated smaller GMV in non-CNS cancer survivals treated with chemotherapy, including right medial, dorsolateral and medial orbital superior frontal gyrus, as compared with non-CNS cancer survivals not treated with chemotherapy and healthy controls. The prefrontal cortex plays an important role in multiple higher cognitive functions such as attention, working memory, language, and executive functions [5].Our findings are in agreement with the pattern of results from neuroimaging studies of cancer survivals treated with chemotherapy showing abnormal structure and function in prefrontal areas [1, 6]. We also detected grey matter reductions in left superior temporal gyrus (STG). The STG has been thought associated with social cognition process in previous studies [7, 8]. It is noteworthy that the STG, combining with amygdala and prefrontal cortex, was demonstrated as an important pathway involved in regulatory system in social cognition [9, 10]. Therefore, combining with our previous findings on grey matter reductions in prefrontal cortex, it is suggested that the structural changes in “prefrontal-STG” pathway may play a crucial role in the mechanism of cognitive impairments in cancer patients treated with chemotherapy.

Conclusion:

The present results suggested that non-CNS cancer survivals treated with chemotherapy exhibit widespread grey matter abnormalities in brain, especially in prefrontal-temporal pathway, which was significantly affected by the time length since chemotherapy. This pattern of grey matter volume changes might improve our understanding of the pathophysiological nature of chemobrain.

Acknowledgements

No acknowledgement found.

References

1. Simó, M., et al., Chemobrain: a systematic review of structural and functional neuroimaging studies. Neuroscience & Biobehavioral Reviews, 2013. 37(8): p. 1311-1321.

2. Myers, J.S., Chemotherapy-related cognitive impairment: the breast cancer experience. Oncol Nurs Forum, 2012. 39(1): p. E31-40.

3. Rust, C. and C. Davis, Chemobrain in underserved African American breast cancer survivors: a qualitative study. Clin J Oncol Nurs, 2013. 17(2): p. E29-34.

4. Egger, M., et al., Bias in meta-analysis detected by a simple, graphical test. Bmj, 1997. 315(7109): p. 629-34.

5. Szczepanski, S.M. and R.T. Knight, Insights into human behavior from lesions to the prefrontal cortex. Neuron, 2014. 83(5): p. 1002-18.

6. Li, M. and K. Caeyenberghs, Longitudinal assessment of chemotherapy-induced changes in brain and cognitive functioning: A systematic review. Neurosci Biobehav Rev, 2018. 92: p. 304-317. 7. Pelphrey, K.A., R.J. Viola, and G. McCarthy, When strangers pass: processing of mutual and averted social gaze in the superior temporal sulcus. Psychol Sci, 2004. 15(9): p. 598-603.

8. Ruby, P. and J. Decety, How would you feel versus how do you think she would feel? A neuroimaging study of perspective-taking with social emotions. J Cogn Neurosci, 2004. 16(6): p. 988-99. 9. Adolphs, R., Cognitive neuroscience of human social behaviour. Nat Rev Neurosci, 2003. 4(3): p. 165-78.

10. Takahashi, H., et al., Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study. Neuroimage, 2004. 23(3): p. 967-74.

Figures

Flow chart showing the results of the identification and attrition of included studies in the present meta-analysis. Abbreviations: CNS, central nervous system; ROI, region of interest

Regional differences of GMV between patients with non-CNS cancer survivals treated with chemotherapy and controls

Meta-analytic maps of GMV abnormalities in non-CNS cancer survivals treated with chemotherapy relative to survivals without chemotherapy and healthy controls. All the brain regions showed reduction of grey matter volume, which are indicated in blue. Abbreviations: STG, superior temporal gyrus; FG, right lingual gyrus; SFG.med.orb, superior frontal gyrus, medial orbital; SFG.med, superior frontal gyrus, medial; SFG.dl, superior frontal gyrus, dorsolateral. L, left; R, right.

Subgroup meta-analytic maps of GMV abnormalities in 1.5T or 3.0T MRI. Upper panel indicated the GMV changes in subgroup analysis results of 1.5T MRI and lower indicated that of 3.0T MRI. Abbreviations: SFG.med.orb, superior frontal gyrus, medial orbital; SFG.med, superior frontal gyrus, medial; SFG.dl, superior frontal gyrus, dorsolateral; ACG, anterior cingulate / paracingulate gyri; STG, superior temporal gyrus; FG, fusiform gyrus. L, left; R, right.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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