To longitudinally investigate alterations in cerebral white matter volume as a function of irradiation dose and time after standard radiotherapy in nasopharyngeal carcinoma patients and to determine how these alterations are related to radiotherapy-associated neurocognitive dysfunction.
A total of 120 nasopharyngeal carcinoma patients were included in the present study. Longitudinal structural magnetic resonance imaging was performed at pre-radiotherapy and 1–3, 6, and 9–12 months post-radiotherapy. Twenty healthy controls were recruited and followed up with in parallel. Structural images were processed via FreeSurfer. The Montreal Cognitive Assessment was performed to evaluate cognitive function of the participants. Linear mixed models and general linear models were used to evaluate different trajectories and the relationship between white matter volume and cognition in patients and controls within approximately 12 months of follow-up.
Selective and time-dependent white matter atrophy was observed in the right parahippocampal gyrus, right inferior temporal gyrus, right middle temporal gyrus, right fusiform gyrus, and left insular cortex in post-radiotherapy patients compared to the controls. Moreover, radiotherapy-associated white matter atrophy in the right parahippocampal gyrus exhibited a dose-dependent pattern, whereas radiotherapy-associated white matter atrophy in the right inferior temporal gyrus was correlated with progressive cognitive impairment in patients.
Taken together, our findings illustrate that white matter volume alterations can be used as a potential biomarker to detect radiotherapy-related subtle brain injury in nasopharyngeal carcinoma patients, which may help further elucidate the pathogenesis of radiation-induced cognitive decline and facilitate studies on cognition-sparing radiotherapy.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
magnetic resonance imaging
Montreal Cognitive Assessment
inferior temporal gyrus
middle temporal gyrus
diffusion tensor imaging
American Joint Committee on Cancer
intensity-modulated radiation therapy
three-dimensional brain volume imaging
estimated total intracranial volume
linear mixed model
general linear model
Balentova, S., & Adamkov, M. (2015). Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review. International Journal of Molecular Sciences, 16(11), 27796–27815.
Buckner, R. L., Sepulcre, J., Talukdar, T., Krienen, F. M., Liu, H., Hedden, T., et al. (2009). Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer’s Disease. Journal of Neuroscience, 29(6), 1860–1873.
Chapman, C. H., Nagesh, V., Sundgren, P. C., Buchtel, H., Chenevert, T. L., Junck, L., et al. (2012). Diffusion Tensor Imaging of Normal-Appearing White Matter as Biomarker for Radiation-Induced Late Delayed Cognitive Decline. International Journal of Radiation Oncology Biology Physics, 82(5), 2033–2040.
Chen, Q., Lv, X., Zhang, S., Lin, J., Song, J., Cao, B., et al. (2020). Altered properties of brain white matter structural networks in patients with nasopharyngeal carcinoma after radiotherapy. Brain Imaging Behav, 14(6), 2745–2761. https://doi.org/10.1007/s11682-019-00224-2.
Cnaan, A., Laird, N. M., & Slasor, P. (1997). Using the general linear mixed model to analyse unbalanced repeated measures and longitudinal data. Statistics in medicine, 16(20), 2349–2380.
Connor, M., Karunamuni, R., McDonald, C., White, N., Pettersson, N., Moiseenko, V., et al. (2016). Dose-dependent white matter damage after brain radiotherapy. Radiotherapy and Oncology, 121(2), 209–216.
Connor, M., Karunamuni, R., McDonald, C., Seibert, T., White, N., Moiseenko, V., et al. (2017). Regional susceptibility to dose-dependent white matter damage after brain radiotherapy. Radiotherapy and Oncology, 123(2), 209–217.
Dien, J., Brian, E. S., Molfese, D. L., & Gold, B. T. (2013). Combined ERP/fMRI evidence for early word recognition effects in the posterior inferior temporal gyrus. Cortex, 49(9), 2307–2321.
Duan, F., Cheng, J., Jiang, J., Chang, J., Zhang, Y., & Qiu, S. (2016). Whole-brain changes in white matter microstructure after radiotherapy for nasopharyngeal carcinoma: a diffusion tensor imaging study. Eur Arch Otorhinolaryngol, 273(12), 4453–4459. https://doi.org/10.1007/s00405-016-4127-x.
Furuse, M., Nonoguchi, N., Kawabata, S., Miyatake, S.-I., & Kuroiwa, T. (2015). Delayed brain radiation necrosis: pathological review and new molecular targets for treatment. Medical Molecular Morphology, 48(4), 183–190.
Gommlich, A., Raschke, F., Wahl, H., & Troost, E. G. C. (2018). Retrospective assessment of MRI-based volumetric changes of normal tissues in glioma patients following radio(chemo)therapy. Clinical and translational radiation oncology, 8, 17–21.
Greene-Schloesser, D., Moore, E., & Robbins, M. E. (2013). Molecular Pathways: Radiation-Induced Cognitive Impairment. Clinical Cancer Research, 19(9), 2294–2300.
Guo, Z., Han, L., Yang, Y., He, H., Li, J., Chen, H., et al. (2018). Longitudinal brain structural alterations in patients with nasopharyngeal carcinoma early after radiotherapy. Neuroimage-Clinical, 19, 252–259.
Jacob, J., Durand, T., Feuvret, L., Mazeron, J.-J., Delattre, J.-Y., Khe, H.-X., et al. (2018). Cognitive impairment and morphological changes after radiation therapy in brain tumors: A review. Radiotherapy and Oncology, 128(2), 221–228.
Karunamuni, R., Bartsch, H., White, N. S., Moiseenko, V., Carmona, R., Marshall, D. C., et al. (2016). Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma. International Journal of Radiation Oncology Biology Physics, 94(2), 297–304.
Kassubek, R., Gorges, M., Westhoff, M. A., Ludolph, A. C., Kassubek, J., & Müller, H. P. (2017). Cerebral microstructural alterations after radiation therapy in high-grade glioma: a diffusion tensor imaging-based study. Front Neurol, 8, 286. https://doi.org/10.3389/fneur.2017.00286.
Klos, J., van Laar, P. J., Sinnige, P. F., Enngti, R. H., Kramer, M. C. A., van der Weide, H. L., et al. (2019). Quantifying effects of radiotherapy-induced microvascular injury; review of established and emerging brain MRI techniques. Radiotherapy and Oncology, 140, 41–53.
Leng, X., Fang, P., Lin, H., An, J., Tan, X., Zhang, C., et al. (2017). Structural MRI research in patients with nasopharyngeal carcinoma following radiotherapy: A DTI and VBM study. Oncol Lett, 14(5), 6091–6096. https://doi.org/10.3892/ol.2017.6968.
Leng, X., Fang, P., Lin, H., Qin, C., Tan, X., Liang, Y., et al. (2019). Application of a machine learning method to whole brain white matter injury after radiotherapy for nasopharyngeal carcinoma. Cancer Imaging, 19(1), 19. https://doi.org/10.1186/s40644-019-0203-y.
Lin, N. U., Wefel, J. R. S., Lee, E. Q., Schiff, D., van den Bent, M. J., Soffietti, R., et al. (2013). Challenges relating to solid tumour brain metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life outcomes. A report from the RANO group. Lancet Oncology, 14(10), E407–E416.
Ljubimova, N. V., Levitman, M. K., Plotnikova, E. D., & Eidus, L. K. (1991). Endothelial cell population dynamics in rat brain after local irradiation. The British journal of radiology, 64(766), 934–940.
Lv, X. F., Zheng, X. L., Zhang, W. D., Liu, L. Z., Zhang, Y. M., Chen, M. Y., & Li, L. (2014). Radiation-induced changes in normal-appearing gray matter in patients with nasopharyngeal carcinoma: a magnetic resonance imaging voxel-based morphometry study. Neuroradiology, 56(5), 423–430. https://doi.org/10.1007/s00234-014-1338-y.
Lv, X., He, H., Yang, Y., Han, L., Guo, Z., Chen, H., et al. (2019). Radiation-induced hippocampal atrophy in patients with nasopharyngeal carcinoma early after radiotherapy: a longitudinal MR-based hippocampal subfield analysis. Brain Imaging and Behavior, 13(4), 1160–1171.
Makale, M. T., McDonald, C. R., Hattangadi-Gluth, J. A., & Kesari, S. (2017). Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours. Nature Reviews Neurology, 13(1), 52–64.
Ng, K. K., Qiu, Y., Lo, J. C.-Y., Koay, E. S.-C., Koh, W.-P., Chee, M. W.-L., & Zhou, J. (2018). Functional segregation loss over time is moderated by APOE genotype in healthy elderly. Human Brain Mapping, 39(7), 2742–2752.
Noppeney, U., & Price, C. J. (2002). Retrieval of visual, auditory, and abstract semantics. NeuroImage, 15(4), 917–926.
Peiffer, A. M., Creer, R. M., Linville, C., Olson, J., Kulkarni, P., Brown, J. A., et al. (2014). Radiation-induced cognitive impairment and altered diffusion tensor imaging in a juvenile rat model of cranial radiotherapy. International Journal of Radiation Biology, 90(9), 799–806.
Petr, J., Platzek, I., Hofheinz, F., Mutsaerts, H. J. M. M., Asllani, I., van Osch, M. J. P., et al. (2018). Photon vs. proton radiochemotherapy: Effects on brain tissue volume and perfusion. Radiotherapy and Oncology, 128(1), 121–127.
Prust, M. J., Jafari-Khouzani, K., Kalpathy-Cramer, J., Polaskova, P., Batchelor, T. T., Gerstner, E. R., & Dietrich, J. (2015). Standard chemoradiation for glioblastoma results in progressive brain volume loss. Neurology, 85(8), 683–691.
Prust, M. L., Jafari-Khouzani, K., Kalpathy-Cramer, J., Polaskova, P., Batchelor, T. T., Gerstner, E. R., & Dietrich, J. (2018). Standard chemoradiation in combination with VEGF targeted therapy for glioblastoma results in progressive gray and white matter volume loss. Neuro-Oncology, 20(2), 289–291.
Qiu, Y., Guo, Z., Han, L., Yang, Y., Li, J., Liu, S., & Lv, X. (2018). Network-level dysconnectivity in patients with nasopharyngeal carcinoma (NPC) early post-radiotherapy: longitudinal resting state fMRI study. Brain Imaging Behav, 12(5), 1279–1289. https://doi.org/10.1007/s11682-017-9801-0.
Raschke, F., Wesemann, T., Wahl, H., Appold, S., Krause, M., Linn, J., & Troost, E. G. C. (2019). Reduced diffusion in normal appearing white matter of glioma patients following radio(chemo)therapy. Radiotherapy and Oncology, 140, 110–115.
Singer, J. W., & Willet, J. (2003). Applied longitudinal data analysis: Modeling change and event occurrence. New York: Oxford University Press.
Soussain, C., Ricard, D., Fike, J. R., Mazeron, J.-J., Psimaras, D., & Delattre, J.-Y. (2009). CNS complications of radiotherapy and chemotherapy. Lancet, 374(9701), 1639–1651.
Steele, J. S. (2013). Longitudinal Data Analysis for the Behavioral Sciences Using R. Structural Equation Modeling-a Multidisciplinary Journal, 20(1), 175–180.
Tang, L.-L., Chen, W.-Q., Xue, W.-Q., He, Y.-Q., Zheng, R.-S., Zeng, Y.-X., & Jia, W.-H. (2016). Global trends in incidence and mortality of nasopharyngeal carcinoma. Cancer Letters, 374(1), 22–30.
Wang, H. Z., Qiu, S. J., Lv, X. F., Wang, Y. Y., Liang, Y., Xiong, W. F., & Ouyang, Z. B. (2012). Diffusion tensor imaging and H-1-MRS study on radiation-induced brain injury after nasopharyngeal carcinoma radiotherapy. Clinical Radiology, 67(4), 340–345.
Wang, J., Chen, H., Liang, H., Wang, W., Liang, Y., Liang, Y., & Zhang, Y. (2019). Low-Frequency Fluctuations Amplitude Signals Exhibit Abnormalities of Intrinsic Brain Activities and Reflect Cognitive Impairment in Leukoaraiosis Patients. Medical Science Monitor, 25, 5219–5228.
Wei, K. R., Zheng, R. S., Zhang, S. W., Liang, Z. H., Li, Z. M., & Chen, W. Q. (2017). Nasopharyngeal carcinoma incidence and mortality in China, 2013. Chin J Cancer, 36(1), 90. https://doi.org/10.1186/s40880-017-0257-9.
Xie, Y., Huang, H., Guo, J., & Zhou, D. (2018). Relative cerebral blood volume is a potential biomarker in late delayed radiation-induced brain injury. Journal of Magnetic Resonance Imaging, 47(4), 1112–1118.
Xiong, W. F., Qiu, S. J., Wang, H. Z., & Lv, X. F. (2013). 1H-MR spectroscopy and diffusion tensor imaging of normal-appearing temporal white matter in patients with nasopharyngeal carcinoma after irradiation: Initial experience. Journal of Magnetic Resonance Imaging, 37(1), 101–108.
Xu, C., Zhang, L.-H., Chen, Y.-P., Liu, X., Zhou, G.-Q., Lin, A.-H., et al. (2017). Chemoradiotherapy Versus Radiotherapy Alone in Stage II Nasopharyngeal Carcinoma: A Systemic Review and Meta-analysis of 2138 Patients. Journal of Cancer, 8(2), 287–297.
Yang, T., Wu, S. L., Liang, J. C., Rao, Z. R., & Ju, G. (2000). Time-dependent astroglial changes after gamma knife radiosurgery in the rat forebrain. Neurosurgery, 47(2), 407–415 discussion 415–406.
Yang, Y., Lin, X., Li, J., Han, L., Li, Z., Liu, S., . . . Qiu, Y. (2019). Aberrant brain activity at early delay stage post-radiotherapy as a biomarker for predicting neurocognitive dysfunction late-delayed in patients with nasopharyngeal carcinoma. Front Neurol, 10, 752. https://doi.org/10.3389/fneur.2019.00752.
Zhang, Y., Yi, X., Gao, J., Li, L., Liu, L., Qiu, T., et al. (2019). Chemotherapy Potentially Facilitates the Occurrence of Radiation Encephalopathy in Patients With Nasopharyngeal Carcinoma Following Radiotherapy: A Multiparametric Magnetic Resonance Imaging Study. Front Oncol, 9, 567. https://doi.org/10.3389/fonc.2019.00567.
We thank LetPub (www.LetPub.com) for its linguistic assistance during the preparation of this manuscript.
This work was funded by grants from the Natural Science Foundation of China (grant numbers 81401399, 81560283, and 81201084) and Natural Science Foundation of Guangdong (grant numbers 2019A1515011143, 2020A1515011332).
This study was conducted in accordance with the recommendations of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and the Institutional Review Board of the Sun Yat-sen University Cancer Center.
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Lin, X., Tang, L., Li, M. et al. Irradiation-related longitudinal white matter atrophy underlies cognitive impairment in patients with nasopharyngeal carcinoma. Brain Imaging and Behavior (2021). https://doi.org/10.1007/s11682-020-00441-0