Irradiation-related longitudinal white matter atrophy underlies cognitive impairment in patients with nasopharyngeal carcinoma


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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4





nasopharyngeal carcinoma;


magnetic resonance imaging


white matter


Montreal Cognitive Assessment


parahippocampal gyrus


inferior temporal gyrus


middle temporal gyrus




early-delayed stage


late-delayed stage


diffusion tensor imaging


fractional anisotrophy


gray matter


American Joint Committee on Cancer


intensity-modulated radiation therapy


three-dimensional brain volume imaging


estimated total intracranial volume


linear mixed model


general linear model


1H-MR spectroscopy.


  1. 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.

    CAS  Article  Google Scholar 

  2. 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.

    CAS  Article  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. 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.

    CAS  Article  Google Scholar 

  6. 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.

    Article  Google Scholar 

  7. 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.

    Article  Google Scholar 

  8. 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.

    Article  Google Scholar 

  9. 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.

    Article  PubMed  Google Scholar 

  10. 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.

    CAS  Article  Google Scholar 

  11. 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.

    Article  Google Scholar 

  12. Greene-Schloesser, D., Moore, E., & Robbins, M. E. (2013). Molecular Pathways: Radiation-Induced Cognitive Impairment. Clinical Cancer Research, 19(9), 2294–2300.

    CAS  Article  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. 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.

    Article  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. 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.

  17. 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.

    Article  Google Scholar 

  18. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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.

    Article  Google Scholar 

  21. 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.

    CAS  Article  Google Scholar 

  22. 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.

    Article  PubMed  Google Scholar 

  23. 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.

    Article  Google Scholar 

  24. 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.

    CAS  Article  Google Scholar 

  25. 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.

    Article  Google Scholar 

  26. Noppeney, U., & Price, C. J. (2002). Retrieval of visual, auditory, and abstract semantics. NeuroImage, 15(4), 917–926.

    CAS  Article  Google Scholar 

  27. 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.

    CAS  Article  Google Scholar 

  28. 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.

    Article  Google Scholar 

  29. 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.

    CAS  Article  Google Scholar 

  30. 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.

    CAS  Article  Google Scholar 

  31. 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.

    Article  PubMed  Google Scholar 

  32. 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.

    CAS  Article  Google Scholar 

  33. Singer, J. W., & Willet, J. (2003). Applied longitudinal data analysis: Modeling change and event occurrence. New York: Oxford University Press.

    Google Scholar 

  34. 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.

    CAS  Article  Google Scholar 

  35. Steele, J. S. (2013). Longitudinal Data Analysis for the Behavioral Sciences Using R. Structural Equation Modeling-a Multidisciplinary Journal, 20(1), 175–180.

    Article  Google Scholar 

  36. 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.

    CAS  Article  Google Scholar 

  37. 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.

    Article  Google Scholar 

  38. 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.

    Article  Google Scholar 

  39. 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.

  40. 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.

    Article  Google Scholar 

  41. 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.

    Article  Google Scholar 

  42. 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.

    Article  Google Scholar 

  43. 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.

    CAS  Article  Google Scholar 

  44. 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.

  45. 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.

    Article  PubMed  PubMed Central  Google Scholar 

Download references


We thank LetPub ( 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).

Author information




XLv and YQiu proposed conceptions and designed the study. XLin conducted data collection and wrote the manuscript. LTang and MLi screened clinical data and original imaging data of the study. MWang collected dose data of the study. YQiu, XLv, and ZGuo performed data analysis and contributed to the revision of this manuscript.

Corresponding authors

Correspondence to Xiaofei Lv or Yingwei Qiu.

Ethics declarations

Ethical approval

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

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information


(DOCX 163 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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).

Download citation


  • Radiotherapy
  • NPC
  • MRI
  • Structural
  • Cognition