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Neuroimaging advances in chemotherapy-related cognitive impairment: from clinical to preclinical research

Abstract

Chemotherapy-related cognitive impairment (CRCI) is a common complication in patients with non-central nervous system malignancies after chemotherapy and significantly impacts the quality of life of survivors. It is essential to understand the neuroimaging mechanism of CRCI to provide a theoretical basis for clinical rehabilitation strategies as the number of survivors at risk for acute and long-term CRCI is increasing dramatically. In this review, we summarize the main neuroimaging features and findings of clinical patients and preclinical animals with CRCI from structural and functional measurements to molecular imaging, from regional to network-based large-scale analysis, from metabolite concentration to blood perfusion status, and from single-modal group-level statistics to multimodal and individual prediction, with the aim to elaborate on multiple-image signatures of patients and animals with cognitive impairment induced by chemotherapy. In addition, the emerging trend of neuroimaging applications in the comprehensive multimodal and individual prediction in patients with CRCI is addressed. Overall, the review explored the heterogeneity of neuropathological mechanisms of CRCI with neuroimaging technology and verified the findings from clinical to preclinical research. The neuropathological mechanism of CRCI involves abnormal alterations not only in morphology, structure, and functions but also in neuro-electrophysiology, biochemical metabolites, and blood perfusion in related brain regions associated with cognition. We conclude that neuroimaging techniques, particularly multimodal neuroimaging techniques, have great potential in identifying underlying neurobiological alterations associated with CRCI. Longitudinal studies with larger sample sizes combined with individual predictions and molecular imaging technology are still warranted to prove their practical utility for more medications than just chemotherapy.

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References

  1. Grayson B, Leger M, Piercy C, et al. Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents. Behav Brain Res. 2015;285:176–93.

    PubMed  Article  Google Scholar 

  2. Vannorsdall TD. Cognitive Changes Related to Cancer Therapy. Med Clin N Am. 2017;101(6):1115–34.

    PubMed  Article  Google Scholar 

  3. Jim HSL, Phillips KM, Chait S, et al. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol. 2012;30(29):3578–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Raffa RB. A proposed mechanism for chemotherapy-related cognitive impairment (‘chemo-fog’). J Clin Pharm Ther. 2011;36(3):257–9.

    CAS  PubMed  Article  Google Scholar 

  5. Cerulla Torrente N, Navarro Pastor J, de la Osa Chaparro N. Systematic review of cognitive sequelae of non-central nervous system cancer and cancer therapy. J Cancer Surviv. 2020;14(4):464–82.

    PubMed  Article  Google Scholar 

  6. Wefel JS, Vardy J, Ahles T, et al. International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol. 2011;12(7):703–8.

    PubMed  Article  Google Scholar 

  7. Cheung YT, Lim SR, Ho HK, et al. Cytokines as mediators of chemotherapy-associated cognitive changes: current evidence, limitations and directions for future research. Plos One. 2013;8(12): e81234.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Ongnok B, Chattipakorn N, Chattipakorn SC. Doxorubicin and cisplatin induced cognitive impairment: the possible mechanisms and interventions. Exp Neurol. 2020;324:113118.

    CAS  PubMed  Article  Google Scholar 

  9. Deprez S, Kesler SR, Saykin AJ, et al. International cognition and cancer task force recommendations for neuroimaging methods in the study of cognitive impairment in non-CNS cancer patients. JNCI J Natl Cancer Inst. 2018;110(3):223–31.

    PubMed  Article  Google Scholar 

  10. Wang X, Huang W, Su L, et al. Neuroimaging advances regarding subjective cognitive decline in preclinical Alzheimer’s disease. Mol Neurodegener. 2020;15(1):1–27.

    Article  CAS  Google Scholar 

  11. Walczak P, Janowski M. Chemobrain as a product of growing success in chemotherapy—focus on glia as both a victim and a cure. Neuropsychiatry. 2019;9(1):2207–16.

    PubMed  PubMed Central  Article  Google Scholar 

  12. Seigers R, Fardell JE. Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev. 2011;35(3):729–41.

    PubMed  Article  Google Scholar 

  13. Silberfarb PM, Philibert D, Levine PM. Psychosocial aspects of neoplastic disease: II. Affective and cognitive effects of chemotherapy in cancer patients. Am J Psychiatry. 1980;137(5):597–601.

    CAS  PubMed  Article  Google Scholar 

  14. van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst. 1998;90(3):210–8.

    PubMed  Article  Google Scholar 

  15. Freeman JR, Broshek DK. Assessing cognitive dysfunction in breast cancer: what are the tools? Clin Breast Cancer. 2002;3:S91–9.

    PubMed  Article  Google Scholar 

  16. Harder H, Holtel H, Bromberg JEC, et al. Cognitive status and quality of life after treatment for primary CNS lymphoma. Neurology. 2004;62(4):544–7.

    CAS  PubMed  Article  Google Scholar 

  17. Schagen SB, Boogerd W, Muller MJ, et al. Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with testicular cancer. Acta Oncol. 2009;47(1):63–70.

    Article  CAS  Google Scholar 

  18. Cheng H, Yang Z, Dong B, et al. Chemotherapy-induced prospective memory impairment in patients with breast cancer. Psychooncology. 2013;22(10):2391–5.

    PubMed  Article  Google Scholar 

  19. Winocur G, Johnston I, Castel H. Chemotherapy and cognition: International cognition and cancer task force recommendations for harmonising preclinical research. Cancer Treat Rev. 2018;69:72–83.

    PubMed  Article  Google Scholar 

  20. Bolton G, Isaacs A. Women’s experiences of cancer-related cognitive impairment, its impact on daily life and care received for it following treatment for breast cancer. Psychol Health Med. 2018;23(10):1261–74.

    PubMed  Article  Google Scholar 

  21. Von Ah D, Tallman EF. Perceived cognitive function in breast cancer survivors: evaluating relationships with objective cognitive performance and other symptoms using the functional assessment of cancer therapy-cognitive function instrument. J Pain Symptom Manage. 2015;49(4):697–706.

    Article  Google Scholar 

  22. Park J, Bae SH, Jung YS, et al. The psychometric properties of the Korean version of the functional assessment of cancer therapy-cognitive (FACT-Cog) in Korean patients with breast cancer. Support Care Cancer. 2015;23(9):2695–703.

    PubMed  Article  Google Scholar 

  23. Dueck AC, Mendoza TR, Mitchell SA, et al. Validity and reliability of the US National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). JAMA Oncol. 2015;1(8):1051.

    PubMed  PubMed Central  Article  Google Scholar 

  24. Moore K, Stutzman S, Priddy L, et al. A pilot study exploring the severity and onset of chemotherapy-related cognitive impairment. Clin J Oncol Nurs. 2019;23(4):411–6.

    PubMed  Article  Google Scholar 

  25. Shilling V, Jenkins V, Trapala IS. The (mis)classification of chemo-fog-methodological inconsistencies in the investigation of cognitive impairment after chemotherapy. Breast Cancer Res Treat. 2006;95(2):125–9.

    PubMed  Article  Google Scholar 

  26. Vardy J, Wong K, Yi Q, et al. Assessing cognitive function in cancer patients. Support Care Cancer. 2006;14(11):1111–8.

    PubMed  Article  Google Scholar 

  27. Gifford AR, Lawrence JA, Baker LD, et al. National Institute on Aging/Alzheimer’s association criteria for mild cognitive impairment applied to chemotherapy treated breast cancer survivors. J Oncol Res. 2017;1(1):101.

    Google Scholar 

  28. Dyk KV, Crespi CM, Petersen L, et al. Identifying cancer-related cognitive impairment using the FACT-Cog perceived cognitive impairment. JNCI Cancer Spectrum. 2020;4(1):pkz099.

    PubMed  Article  Google Scholar 

  29. Collins B, Mackenzie J, Kyeremanteng C. Study of the cognitive effects of chemotherapy: Considerations in selection of a control group. J Clin Exp Neuropsyc. 2013;35(4):435–44.

    Article  Google Scholar 

  30. Nelson WL, Suls J. New approaches to understand cognitive changes associated with chemotherapy for non-central nervous system tumors. J Pain Symptom Manage. 2013;46(5):707–21.

    PubMed  Article  Google Scholar 

  31. O’Farrell E, Smith A, Collins B. Objective-subjective disparity in cancer-related cognitive impairment: does the use of change measures help reconcile the difference? Psychooncology. 2017;26(10):1667–74.

    PubMed  Article  Google Scholar 

  32. Lee GD. Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin Cancer Res. 2006;12(1):198–205.

    CAS  PubMed  Article  Google Scholar 

  33. Fardell JE, Vardy J, Monds LA, et al. The long-term impact of oxaliplatin chemotherapy on rodent cognition and peripheral neuropathy. Behav Brain Res. 2015;291:80–8.

    CAS  PubMed  Article  Google Scholar 

  34. Rendeiro C, Sheriff A, Bhattacharya TK, et al. Long-lasting impairments in adult neurogenesis, spatial learning and memory from a standard chemotherapy regimen used to treat breast cancer. Behav Brain Res. 2016;315:10–22.

    PubMed  Article  Google Scholar 

  35. Chiang ACA, Huo X, Kavelaars A, et al. Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment. Brain Behav Immun. 2019;79:319–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Li C, Niu J, Zhou B, et al. Dexmedetomidine attenuates cisplatin-induced cognitive impairment by modulating miR-429-3p expression in rats. 3 Biotech. 2020;10(6):244.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Deyama S, Li X, Duman RS. Neuron-specific deletion of VEGF or its receptor Flk-1 impairs recognition memory. Eur Neuropsychopharm. 2020;31:145–51.

    CAS  Article  Google Scholar 

  38. Moore HC, Parsons MW, Yue GH, et al. Electroencephalogram power changes as a correlate of chemotherapy-associated fatigue and cognitive dysfunction. Support Care Cancer. 2014;22(8):2127–31.

    PubMed  Article  Google Scholar 

  39. Schagen SB, Hamburger HL, Muller MJ, et al. Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. J Neurooncol. 2001;51(2):159–65.

    CAS  PubMed  Article  Google Scholar 

  40. Kreukels BP, van Dam FS, Ridderinkhof KR, et al. Persistent neurocognitive problems after adjuvant chemotherapy for breast cancer. Clin Breast Cancer. 2008;8(1):80–7.

    CAS  PubMed  Article  Google Scholar 

  41. Simó M, Gurtubay-Antolin A, Vaquero L, et al. Performance monitoring in lung cancer patients pre- and post-chemotherapy using fine-grained electrophysiological measures. NeuroImage Clin. 2018;18:86–96.

    PubMed  Article  Google Scholar 

  42. Perrier J, Viard A, Levy C, et al. Longitudinal investigation of cognitive deficits in breast cancer patients and their gray matter correlates: impact of education level. Brain Imaging Behav. 2020;14(1):226–41.

    PubMed  Article  Google Scholar 

  43. Henneghan A, Rao V, Harrison RA, et al. Cortical brain age from pre-treatment to post-chemotherapy in patients with breast cancer. Neurotox Res. 2020;37(4):788–99.

    PubMed  PubMed Central  Article  Google Scholar 

  44. Chen BT, Sethi SK, Jin T, et al. Assessing brain volume changes in older women with breast cancer receiving adjuvant chemotherapy: a brain magnetic resonance imaging pilot study. Breast Cancer Res. 2018;20(1):38.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. Kesler S, Janelsins M, Koovakkattu D, et al. Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain Behav Immun. 2013;30:S109–16.

    CAS  PubMed  Article  Google Scholar 

  46. Lepage C, Smith AM, Moreau J, et al. A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients. Springerplus. 2014;3:444.

    PubMed  PubMed Central  Article  Google Scholar 

  47. Apple AC, Ryals AJ, Alpert KI, et al. Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns. Neuroimage Clin. 2017;14:685–91.

    PubMed  PubMed Central  Article  Google Scholar 

  48. Li X, Chen H, Lv Y, et al. Diminished gray matter density mediates chemotherapy dosage-related cognitive impairment in breast cancer patients. Sci Rep UK. 2018;8(1):13801.

    Article  CAS  Google Scholar 

  49. Amidi A, Agerbæk M, Wu LM, et al. Changes in cognitive functions and cerebral grey matter and their associations with inflammatory markers, endocrine markers, and APOE genotypes in testicular cancer patients undergoing treatment. Brain Imaging Behav. 2017;11(3):769–83.

    PubMed  Article  Google Scholar 

  50. Shiroishi MS, Gupta V, Bigjahan B, et al. Brain cortical structural differences between non-central nervous system cancer patients treated with and without chemotherapy compared to non-cancer controls: a cross-sectional pilot MRI study using clinically-indicated scans. Proc SPIE Int Soc Opt Eng. 2017;10572:105720G.

    PubMed  PubMed Central  Google Scholar 

  51. Sales M, Suemoto CK, Apolinario D, et al. Effects of adjuvant chemotherapy on cognitive function of patients with early-stage colorectal cancer. Clin Colorectal Cancer. 2019;18(1):19–27.

    PubMed  Article  Google Scholar 

  52. Deprez S, Amant F, Yigit R, et al. Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp. 2011;32(3):480–93.

    PubMed  Article  Google Scholar 

  53. Deprez S, Amant F, Smeets A, et al. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol. 2012;30(3):274–81.

    PubMed  Article  Google Scholar 

  54. Mzayek Y, de Ruiter MB, Oldenburg HSA, et al. Measuring decline in white matter integrity after systemic treatment for breast cancer: omitting skeletonization enhances sensitivity. Brain Imaging Behav. 2020;15(3):1191–200.

    PubMed Central  Article  Google Scholar 

  55. Menning S, de Ruiter MB, Veltman DJ, et al. Changes in brain white matter integrity after systemic treatment for breast cancer: a prospective longitudinal study. Brain Imaging Behav. 2018;12(2):324–34.

    PubMed  Article  Google Scholar 

  56. Chen BT, Ye N, Wong CW, et al. Effects of chemotherapy on aging white matter microstructure: a longitudinal diffusion tensor imaging study. J Geriatr Oncol. 2020;11(2):290–6.

    PubMed  Article  Google Scholar 

  57. Billiet T, Emsell L, Vandenbulcke M, et al. Recovery from chemotherapy-induced white matter changes in young breast cancer survivors? Brain Imaging Behav. 2018;12(1):64–77.

    PubMed  Article  Google Scholar 

  58. Sleurs C, Lemiere J, Christiaens D, et al. Advanced MR diffusion imaging and chemotherapy-related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma? Hum Brain Mapp. 2018;39(8):3375–87.

    PubMed  PubMed Central  Article  Google Scholar 

  59. Inagaki M, Yoshikawa E, Matsuoka Y, et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer Am Cancer Soc. 2007;109(1):146–56.

    Google Scholar 

  60. Simó M, Root JC, Vaquero L, et al. Cognitive and brain structural changes in a lung cancer population. J Thorac Oncol. 2015;10(1):38–45.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. Blommaert J, Schroyen G, Vandenbulcke M, et al. Age-dependent brain volume and neuropsychological changes after chemotherapy in breast cancer patients. Hum Brain Mapp. 2019;40(17):4994–5010.

    PubMed  PubMed Central  Article  Google Scholar 

  62. Kesler SR, Gugel M, Huston-Warren E, et al. Atypical structural connectome organization and cognitive impairment in young survivors of acute lymphoblastic leukemia. Brain Connectivity. 2016;6(4):273–82.

    PubMed  PubMed Central  Article  Google Scholar 

  63. Zeng Y, Cheng ASK, Song T, et al. Subjective cognitive impairment and brain structural networks in Chinese gynaecological cancer survivors compared with age-matched controls: a cross-sectional study. BMC Cancer. 2017;17(1):796.

    PubMed  PubMed Central  Article  Google Scholar 

  64. Amidi A, Hosseini SMH, Leemans A, et al. Changes in brain structural networks and cognitive functions in testicular cancer patients receiving cisplatin-based chemotherapy. JNCI J Natl Cancer Inst 2017;109 (12).

  65. Wang L, Zou L, Chen Q, et al. Gray matter structural network disruptions in survivors of acute lymphoblastic leukemia with chemotherapy treatment. Acad Radiol. 2020;27(3):e27–34.

    PubMed  Article  Google Scholar 

  66. Liu S, Yin N, Ma R, et al. Abnormal topological characteristics of brain white matter network relate to cognitive and emotional deficits of non-small cell lung cancer (NSCLC) patients prior to chemotherapy. Int J Neurosci. 2020;1–10.

  67. de Ruiter MB, Reneman L, Boogerd W, et al. Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Hum Brain Mapp. 2011;32(8):1206–19.

    PubMed  Article  Google Scholar 

  68. Scherling C, Collins B, Mackenzie J, et al. Prechemotherapy differences in response inhibition in breast cancer patients compared to controls: a functional magnetic resonance imaging study. J Clin Exp Neuropsychol. 2012;34(5):543–60.

    PubMed  Article  Google Scholar 

  69. Vardy JL, Stouten-Kemperman MM, Pond G, et al. A mechanistic cohort study evaluating cognitive impairment in women treated for breast cancer. Brain Imaging Behav. 2019;13(1):15–26.

    PubMed  Article  Google Scholar 

  70. Scherling C, Collins B, MacKenzie J, et al. Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an fMRI study. Front Hum Neurosci. 2011;I:5.

    Google Scholar 

  71. Campbell KL, Kam J, Neil-Sztramko SE, et al. Effect of aerobic exercise on cancer-associated cognitive impairment: a proof-of-concept RCT. Psychooncology. 2018;27(1):53–60.

    CAS  PubMed  Article  Google Scholar 

  72. Dumas JA, Makarewicz J, Schaubhut GJ, et al. Chemotherapy altered brain functional connectivity in women with breast cancer: a pilot study. Brain Imaging Behav. 2013;7(4):524–32.

    PubMed  Article  Google Scholar 

  73. Askren MK, Jung M, Berman MG, et al. Neuromarkers of fatigue and cognitive complaints following chemotherapy for breast cancer: a prospective fMRI investigation. Breast Cancer Res Treat. 2014;147(2):445–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Jung MS, Zhang M, Askren MK, et al. Cognitive dysfunction and symptom burden in women treated for breast cancer: a prospective behavioral and fMRI analysis. Brain Imaging Behav. 2017;11(1):86–97.

    PubMed  Article  Google Scholar 

  75. Conroy SK, McDonald BC, Smith DJ, et al. Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage. Breast Cancer Res Treat. 2013;137(2):493–502.

    CAS  PubMed  Article  Google Scholar 

  76. Root JC, Pergolizzi D, Pan H, et al. 2020. Prospective evaluation of functional brain activity and oxidative damage in breast cancer: changes in task-induced deactivation during a working memory task. Brain Imaging Behav.

  77. Wang L, Apple AC, Schroeder MP, et al. Reduced prefrontal activation during working and long-term memory tasks and impaired patient-reported cognition among cancer survivors post chemotherapy compared with healthy controls. Cancer Am Cancer Soc. 2016;122(2):258–68.

    Google Scholar 

  78. Stefancin P, Cahaney C, Parker RI, et al. Neural correlates of working memory function in pediatric cancer survivors treated with chemotherapy: an fMRI study. NMR Biomed. 2020;33(6): e4296.

    PubMed  Article  Google Scholar 

  79. Miao H, Li J, Hu S, et al. Long-term cognitive impairment of breast cancer patients after chemotherapy: a functional MRI study. Eur J Radiol. 2016;85(6):1053–7.

    PubMed  Article  Google Scholar 

  80. Chen BT, Jin T, Patel SK, et al. Intrinsic brain activity changes associated with adjuvant chemotherapy in older women with breast cancer: a pilot longitudinal study. Breast Cancer Res Treat. 2019;176(1):181–9.

    PubMed  PubMed Central  Article  Google Scholar 

  81. Kardan O, Reuter-Lorenz PA, Peltier S, et al. Brain connectivity tracks effects of chemotherapy separately from behavioral measures. Neuroimage Clin. 2019;21:101654.

    PubMed  PubMed Central  Article  Google Scholar 

  82. Chen H, Ding K, Zhao J, et al. The dorsolateral prefrontal cortex is selectively involved in chemotherapy-related cognitive impairment in breast cancer patients with different hormone receptor expression. Am J Cancer Res. 2019;9(8):1776–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Van der Gucht K, Ahmadoun S, Melis M, et al. Effects of a mindfulness-based intervention on cancer-related cognitive impairment: results of a randomized controlled functional magnetic resonance imaging pilot study. Cancer Am Cancer Soc. 2020;126(18):4246–55.

    Google Scholar 

  84. Chen L, Zhan Y, He F, et al. Altered functional connectivity density in young survivors of acute lymphoblastic leukemia using resting-state fMRI. Cancer Manage Res. 2020;12:7033–41.

    Article  Google Scholar 

  85. Chen L, Zhan Y, He F, et al. Altered functional connectivity density in young survivors of acute lymphoblastic leukemia using resting-state fMRI. Cancer Manage Res. 2020;12:7033–41.

    Article  Google Scholar 

  86. Piccirillo JF, Hardin FM, Nicklaus J, et al. Cognitive impairment after chemotherapy related to atypical network architecture for executive control. Oncology. 2015;88(6):360–8.

    CAS  PubMed  Article  Google Scholar 

  87. Kesler SR, Blayney DW. Neurotoxic Effects of anthracycline-vs non anthracycline-based chemotherapy on cognition in breast cancer survivors. JAMA Oncol. 2016;2(2):185.

    PubMed  PubMed Central  Article  Google Scholar 

  88. Cheng H, Li W, Gong L, et al. Altered resting-state hippocampal functional networks associated with chemotherapy-induced prospective memory impairment in breast cancer survivors. Sci Rep UK. 2017;7(1):45135.

    CAS  Article  Google Scholar 

  89. Miao H, Chen X, Yan Y, et al. Functional connectivity change of brain default mode network in breast cancer patients after chemotherapy. Neuroradiology. 2016;8(9):921–8.

    Article  Google Scholar 

  90. Chen VC, Lin K, Tsai Y, et al. Connectome analysis of brain functional network alterations in breast cancer survivors with and without chemotherapy. PLOS One. 2020;15(5): e232548.

    Google Scholar 

  91. Zhang Y, Chen Y, Hu L, et al. Chemotherapy-induced functional changes of the default mode network in patients with lung cancer. Brain Imaging Behav. 2020;14(3):847–56.

    PubMed  Article  Google Scholar 

  92. Feng Y, Wang YF, Zheng LJ, et al. Network-level functional connectivity alterations in chemotherapy treated breast cancer patients: a longitudinal resting state functional MRI study. Cancer Imaging. 2020;20(1):73.

    PubMed  PubMed Central  Article  Google Scholar 

  93. Bruno J, Hosseini SMH, Kesler S. Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis. 2012;48(3):329–38.

    PubMed  PubMed Central  Article  Google Scholar 

  94. Phillips NS, Kesler SR, Scoggins MA, et al. Connectivity of the cerebello-thalamo-cortical pathway in survivors of childhood leukemia treated with chemotherapy only. JAMA Netw Open. 2020;3(11): e2025839.

    PubMed  PubMed Central  Article  Google Scholar 

  95. Daugherty AM, Raz N. Appraising the Role of iron in brain aging and cognition: promises and limitations of MRI methods. Neuropsychol Rev. 2015;25(3):272–87.

    PubMed  PubMed Central  Article  Google Scholar 

  96. Chen BT, Ghassaban K, Jin T, et al. Subcortical brain iron deposition and cognitive performance in older women with breast cancer receiving adjuvant chemotherapy: a pilot MRI study. Magn Reson Imaging. 2018;54:218–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Rodrigue KM, Daugherty AM, Haacke EM, et al. The role of hippocampal iron concentration and hippocampal volume in age-related differences in memory. Cereb Cortex. 2013;23(7):1533–41.

    PubMed  Article  Google Scholar 

  98. McDonald BC, Conroy SK, Smith DJ, et al. Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: a replication and extension study. Brain Behav Immun. 2013;30(Suppl):S117–25.

    PubMed  Article  Google Scholar 

  99. Tong T, Lu H, Zong J, et al. Chemotherapy-related cognitive impairment in patients with breast cancer based on MRS and DTI analysis. Breast Cancer-Tokyo. 2020;27(5):893–902.

    Article  Google Scholar 

  100. Kesler SR, Watson C, Koovakkattu D, et al. Elevated prefrontal myo-inositol and choline following breast cancer chemotherapy. Brain Imaging Behav. 2013;7(4):501–10.

    PubMed  Article  Google Scholar 

  101. Zeng Y, Cheng ASK, Song T, et al. Effects of acupuncture on cancer-related cognitive impairment in Chinese gynecological cancer patients: a pilot cohort study. Integr Cancer Ther. 2018;17(3):737–46.

    PubMed  PubMed Central  Article  Google Scholar 

  102. Ponto LLB, Menda Y, Magnotta VA, et al. Frontal hypometabolism in elderly breast cancer survivors determined by [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET): a pilot study. Int J Geriatr Psych. 2015;30(6):587–94.

    Article  Google Scholar 

  103. Sorokin J, Saboury B, Ahn JA, et al. Adverse functional effects of chemotherapy on whole-brain metabolism: a PET/CT quantitative analysis of FDG metabolic pattern of the “chemo-brain.” Clin Nucl Med. 2014;39(1):e35–9.

    PubMed  Article  Google Scholar 

  104. Baudino B, D’Agata F, Caroppo P, et al. The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients. Q J Nucl Med Mol Imaging. 2012;56(6):559–68.

    CAS  PubMed  Google Scholar 

  105. Eshghi N, Garland LL, Choudhary G, et al. Regional changes in brain (18)F-FDG uptake after prophylactic cranial irradiation and chemotherapy in small cell lung cancer may reflect functional changes. J Nucl Med Technol. 2018;46(4):355–8.

    PubMed  Article  Google Scholar 

  106. Vitor T, Kozasa EH, Bressan RA, et al. Impaired brain dopamine transporter in chemobrain patients submitted to brain SPECT imaging using the technetium-99m labeled tracer TRODAT-1. Ann Nucl Med. 2019;33(4):269–79.

    CAS  PubMed  Article  Google Scholar 

  107. Gandal MJ, Ehrlichman RS, Rudnick ND, et al. A novel electrophysiological model of chemotherapy-induced cognitive impairments in mice. Neuroscience. 2008;157(1):95–104.

    CAS  PubMed  Article  Google Scholar 

  108. Winocur G, Henkelman M, Wojtowicz JM, et al. The effects of chemotherapy on cognitive function in a mouse model: a prospective study. Clin Cancer Res. 2012;18(11):3112–21.

    CAS  PubMed  Article  Google Scholar 

  109. Winocur G, Berman H, Nguyen M, et al. Neurobiological mechanisms of chemotherapy-induced cognitive impairment in a transgenic model of breast cancer. Neuroscience. 2018;369:51–65.

    CAS  PubMed  Article  Google Scholar 

  110. Berlin C, Lange K, Lekaye HC, et al. Long-term clinically relevant rodent model of methotrexate-induced cognitive impairment. Neuro Oncol. 2020;22(8):1126–37.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Speidell AP, Demby T, Lee Y, et al. Development of a human APOE knock-in mouse model for study of cognitive function after cancer chemotherapy. Neurotox Res. 2019;35(2):291–303.

    CAS  PubMed  Article  Google Scholar 

  112. Demby TC, Rodriguez O, McCarthy CW, et al. A mouse model of chemotherapy-related cognitive impairments integrating the risk factors of aging and APOE4 genotype. Behav Brain Res. 2020;384:112534.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Inoue T, Majid T, Pautler RG. Manganese enhanced MRI (MEMRI): neurophysiological applications. Rev Neurosci. 2011;22(6):675–94.

    PubMed  PubMed Central  Article  Google Scholar 

  114. Shi D, Huang Y, Lai CSW, et al. Chemotherapy-induced cognitive impairment is associated with cytokine dysregulation and disruptions in neuroplasticity. Mol Neurobiol. 2019;56(3):2234–43.

    CAS  PubMed  Article  Google Scholar 

  115. Shi D, Huang Y, Lai CSW, et al. Ginsenoside Rg1 prevents chemotherapy-induced cognitive impairment: associations with microglia-mediated cytokines, neuroinflammation, and neuroplasticity. Mol Neurobiol. 2019;56(8):5626–42.

    CAS  PubMed  Article  Google Scholar 

  116. Keeney JTR, Ren X, Warrier G, et al. Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”). Oncotarget. 2018;9(54):30324–39.

    PubMed  PubMed Central  Article  Google Scholar 

  117. Ren X, Keeney JTR, Miriyala S, et al. The triangle of death of neurons: oxidative damage, mitochondrial dysfunction, and loss of choline-containing biomolecules in brains of mice treated with doxorubicin. Advanced insights into mechanisms of chemotherapy induced cognitive impairment (“chemobrain”) involving TNF-α. Free Radic Bio Med. 2019;134:1–8.

    CAS  Article  Google Scholar 

  118. Seigers R, Timmermans J, van der Horn HJ, et al. Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behav Brain Res. 2010;207(2):265–72.

    CAS  PubMed  Article  Google Scholar 

  119. Lim I, Joung H, Yu AR, et al. PET Evidence of the effect of donepezil on cognitive performance in an animal model of chemobrain. Biomed Res Int. 2016;2016:1–7.

    CAS  Google Scholar 

  120. Barry RL, Byun NE, Tantawy MN, et al. In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction. Brain Imaging Behav. 2018;12(1):87–95.

    PubMed  Article  Google Scholar 

  121. Bai X, Zheng J, Zhang B, et al. Cognitive dysfunction and neurophysiological mechanism of breast cancer patients undergoing chemotherapy based on RS fMRI images. World Neurosurg. 2020;149:406–12.

    PubMed  Article  Google Scholar 

  122. Mo C, Lin H, Fu F, et al. Chemotherapy-induced changes of cerebral activity in resting-state functional magnetic resonance imaging and cerebral white matter in diffusion tensor imaging. Oncotarget. 2017;8(46):81273–84.

    PubMed  PubMed Central  Article  Google Scholar 

  123. Kesler SR, Ogg R, Reddick WE, et al. Brain network connectivity and executive function in long-term survivors of childhood acute lymphoblastic leukemia. Brain Connectivity. 2018;8(6):333–42.

    PubMed  PubMed Central  Article  Google Scholar 

  124. Cahaney C, Stefancin P, Coulehan K, et al. Anatomical brain MRI study of pediatric cancer survivors treated with chemotherapy: correlation with behavioral measures. Magn Reson Imaging. 2020;72:8–13.

    PubMed  Article  Google Scholar 

  125. Nudelman KN, Wang Y, McDonald BC, et al. Altered cerebral blood flow one month after systemic chemotherapy for breast cancer: a prospective study using pulsed arterial spin labeling MRI perfusion. PLOS One. 2014;9(5): e96713.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. Kesler SR, Rao A, Blayney DW, et al. Predicting long-term cognitive outcome following breast cancer with pre-treatment resting state fMRI and random forest machine learning. Front Hum Neurosci. 2017;11:555.

    PubMed  PubMed Central  Article  Google Scholar 

  127. Chen VC, Lin TY, Yeh DC, et al. Functional and structural connectome features for machine learning chemo-brain prediction in women treated for breast cancer with chemotherapy. Brain Sci. 2020;10(11):851.

    CAS  PubMed Central  Article  Google Scholar 

  128. Hosseini SM, Kesler SR. Multivariate pattern analysis of FMRI in breast cancer survivors and healthy women. J Int Neuropsychol Soc. 2014;20(4):391–401.

    PubMed  Article  Google Scholar 

  129. Kesler SR, Petersen ML, Rao V, et al. Functional connectome biotypes of chemotherapy-related cognitive impairment. J Cancer Surviv. 2020;14(4):483–93.

    PubMed  PubMed Central  Article  Google Scholar 

  130. Chen VC, Lin TY, Yeh DC, et al. Predicting chemo-brain in breast cancer survivors using multiple MRI features and machine-learning. Magn Reson Med. 2019;81(5):3304–13.

    CAS  PubMed  Article  Google Scholar 

  131. Henneghan AM, Gibbons C, Harrison RA, et al. Predicting patient reported outcomes of cognitive function using connectome-based predictive modeling in breast cancer. Brain Topogr. 2020;33(1):135–42.

    PubMed  Article  Google Scholar 

  132. Iuchi T, Shingyoji M, Sakaida T, et al. Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma. Lung Cancer. 2013;82(2):282–7.

    CAS  PubMed  Article  Google Scholar 

  133. Kurihara M, Koda H, Aono H, et al. Rapidly progressive military brain metastasis of lung cancer after EGFR tyrosine kinase inhibitor discontinuation: an autopsy report. Neuropathology. 2019;39(2):147–55.

    CAS  PubMed  Article  Google Scholar 

  134. Zhu J, Zhou R, Xiao H. Mental disorder or conscious disturbance in epidermal growth factor receptor-tyrosine kinase inhibitor treatment of advanced lung adenocarcinoma. Excli J. 2020;19:230–8.

    PubMed  PubMed Central  Google Scholar 

  135. Peled N, Gillis R, Kilickap S, et al. GLASS: global lorlatinib for ALK (+) and ROS1(+) retrospective study: real world data of 123 NSCLC patients. Lung Cancer. 2020;148:48–54.

    PubMed  Article  Google Scholar 

  136. Lucignani G, Perneczky R. Molecular imaging in cognitive impairment: the relevance of cognitive reserve, importance of multisite longitudinal trials and challenges of standardised analysis. Eur J Nucl Med Mol I. 2010;37(2):399–404.

    Article  Google Scholar 

  137. Albin RL, Burke JF, Koeppe RA, et al. Assessing mild cognitive impairment with amyloid and dopamine terminal molecular imaging. J Nucl Med. 2013;54(6):887–93.

    CAS  PubMed  Article  Google Scholar 

  138. Knezevic D, Mizrahi R. Molecular imaging of neuroinflammation in Alzheimer’s disease and mild cognitive impairment. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80(Pt B):123–31.

    CAS  PubMed  Article  Google Scholar 

  139. Smith GS, Barrett FS, Joo JH, et al. Molecular imaging of serotonin degeneration in mild cognitive impairment. Neurobiol Dis. 2017;105:33–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Johnson KA, Minoshima S, Bohnen NI, et al. Update on appropriate use criteria for amyloid PET imaging: Dementia experts, mild cognitive impairment, and education. Alzheimers Dement. 2013;9(4):e106–9.

    PubMed  Article  Google Scholar 

  141. Lan MJ, Ogden RT, Kumar D, et al. Utility of molecular and structural brain imaging to predict progression from mild cognitive impairment to dementia. J Alzheimers Dis. 2017;60(3):939–47.

    PubMed  PubMed Central  Article  Google Scholar 

  142. Vannini P, Hanseeuw B, Munro CE, et al. Anosognosia for memory deficits in mild cognitive impairment: insight into the neural mechanism using functional and molecular imaging. Neuroimage Clin. 2017;15:408–14.

    PubMed  PubMed Central  Article  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (81720108022, 81971596, and 82171908); supported by the Fundamental Research Funds for the Central Universities, Nanjing University (2020-021414380462); The key project of Jiangsu Commission of Health (K2019025); Key medical talents of the Jiangsu province, the "13th Five-Year" health promotion project of the Jiangsu province (ZDRCA2016064); Jiangsu Provincial Key Medical Discipline (Laboratory) (ZDXKA2016020); and the project of the sixth peak of talented people (WSN -138). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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XH and ML have contributed equally, they were involved in the conceptualisation of the review, and they acquired and analyzed all literature, drafted and revised the manuscript. PL, RL, and ZQ analyzed and explained the results of clinical neuroimaging. XL, QC, JL, and WC analyzed and explained the results of preclinical neuroimaging. ND, YM, and LC analyzed and explained the results of emerging trends in neuroimaging. JZ and XX summarized and revised the manuscript. XZ and BZ designed and revised the manuscript for extremely important intellectual content.

Corresponding author

Correspondence to Bing Zhang.

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Han, X., Li, M., Qing, Z. et al. Neuroimaging advances in chemotherapy-related cognitive impairment: from clinical to preclinical research. Chin J Acad Radiol 5, 151–180 (2022). https://doi.org/10.1007/s42058-022-00096-4

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  • DOI: https://doi.org/10.1007/s42058-022-00096-4

Keywords

  • Chemotherapy-related cognitive impairment
  • Cancers
  • Neuropathological mechanisms
  • MRI
  • Multimodal neuroimaging