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  • Review Article
  • Published:

Cognitive adverse effects of chemotherapy and immunotherapy: are interventions within reach?

Nature Reviews Neurology volume 18, pages 173–185 (2022)Cite this article

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Abstract

One in three people will be diagnosed with cancer during their lifetime. The community of cancer patients is growing, and several common cancers are becoming increasingly chronic; thus, cancer survivorship is an important part of health care. A large body of research indicates that cancer and cancer therapies are associated with cognitive impairment. This research has mainly concentrated on chemotherapy-associated cognitive impairment but, with the arrival of immunotherapies, the focus is expected to widen and the number of studies investigating the potential cognitive effects of these new therapies is rising. Meanwhile, patients with cognitive impairment and their healthcare providers are eagerly awaiting effective approaches to intervene against the cognitive effects of cancer treatment. In this Review, we take stock of the progress that has been made and discuss the steps that need to be taken to accelerate research into the biology underlying cognitive decline following chemotherapy and immunotherapy and to develop restorative and preventive interventions. We also provide recommendations to clinicians on how to best help patients who are currently experiencing cognitive impairment.

Key points

  • A growing number of individuals are being confronted with cognitive impairment resulting from non-CNS cancer and its treatment; this impairment has a large effect on occupational, familial and social lives, resulting in diminished quality of life.

  • Chemotherapy-induced cognitive impairment is multifactorial: different molecular mechanisms result in blood–brain barrier disruption, inflammation, accelerated cellular senescence and neuronal stem cell abnormalities, all of which lead to cognitive impairment.

  • Limited evidence from preclinical and clinical studies suggests that neuroinflammation and activated microglia have an essential role in immunotherapy-related cognitive impairment; future studies of immunotherapy should incorporate cognition endpoints to investigate immunotherapy-related cognitive decline.

  • Pharmacological or behaviour-directed interventions with proven effectiveness for prevention or restoration of cognitive problems in patients with non-CNS cancers are lacking; however, preclinical studies on pharmacological mechanism-directed interventions hold some promise.

  • To identify successful interventions, adequately designed and powered preclinical and clinical trials are required.

  • Prevention and early interventions are likely to be the most effective approaches for maintaining cognitive function; identification of patients at risk of cognitive impairment and development of predictive biomarkers will increase our understanding and facilitate the design of cognitive protection trials.

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Fig. 1: Relationship between objective cognitive function and subjective cognitive concerns.
Fig. 2: Hypotheses on ICI-related cognitive impairment.
Fig. 3: Potential pathophysiology of ICANS and cognitive impairment in CAR T cell therapy.

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References

  1. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    PubMed  Google Scholar 

  2. Miller, K. D. et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin. 69, 363–385 (2019).

    PubMed  Google Scholar 

  3. Mayo, S. J. et al. Cancer-related cognitive impairment in patients with non-central nervous system malignancies: an overview for oncology providers from the MASCC Neurological Complications Study Group. Support. Care Cancer 29, 2821–2840 (2020).

    PubMed  Google Scholar 

  4. Schagen, S. B. et al. Monitoring and optimising cognitive function in cancer patients: present knowledge and future directions. EJC Suppl. 12, 29–40 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Noll, K. R. et al. Monitoring of neurocognitive function in the care of patients with brain tumors. Curr. Treat. Options Neurol. 21, 33 (2019).

    PubMed  Google Scholar 

  6. Matsos, A. & Johnston, I. N. Chemotherapy-induced cognitive impairments: a systematic review of the animal literature. Neurosci. Biobehav. Rev. 102, 382–399 (2019). A systematic evaluation of cognitive domains and underlying neural mechanisms disrupted by chemotherapy of various classes.

    CAS  PubMed  Google Scholar 

  7. Deprez, S. et al. International cognition and cancer task force recommendations for neuroimaging methods in the study of cognitive impairment in non-CNS cancer patients. J. Natl. Cancer Inst. 110, 223–231 (2018). Recommendations for MRI sequences to facilitate increased use of neuroimaging in studies on cancer and cognition.

    PubMed  PubMed Central  Google Scholar 

  8. Gibson, E. M. & Monje, M. Emerging mechanistic underpinnings and therapeutic targets for chemotherapy-related cognitive impairment. Curr. Opin. Oncol. 31, 531–539 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Gibson, E. M. & Monje, M. Microglia in cancer therapy-related cognitive impairment. Trends Neurosci. 44, 441–451 (2021).

    CAS  PubMed  Google Scholar 

  10. Ahles, T. A., Root, J. C. & Ryan, E. L. Cancer- and cancer treatment-associated cognitive change: an update on the state of the science. J. Clin. Oncol. 30, 3675–3686 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Wefel, J. S. et al. A prospective study of cognitive function in men with non-seminomatous germ cell tumors. Psychooncology 23, 626–633 (2014).

    PubMed  Google Scholar 

  12. Correa, D. D. et al. Cognitive functions in long-term survivors of ovarian cancer. Gynecol. Oncol. 119, 366–369 (2010).

    PubMed  Google Scholar 

  13. Gonzalez, B. D. et al. Course and predictors of cognitive function in patients with prostate cancer receiving androgen-deprivation therapy: a controlled comparison. J. Clin. Oncol. 33, 2021–2027 (2015).

    PubMed  PubMed Central  Google Scholar 

  14. Cruzado, J. A. et al. Longitudinal study of cognitive dysfunctions induced by adjuvant chemotherapy in colon cancer patients. Support. Care Cancer 22, 1815–1823 (2014).

    PubMed  Google Scholar 

  15. Underwood, E. A. et al. Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis. Breast Cancer Res. Treat. 168, 299–310 (2018).

    CAS  PubMed  Google Scholar 

  16. Touat, M., Talmasov, D., Ricard, D. & Psimaras, D. Neurological toxicities associated with immune-checkpoint inhibitors. Curr. Opin. Neurol. 30, 659–668 (2017).

    CAS  PubMed  Google Scholar 

  17. Bartels, F. et al. Neuronal autoantibodies associated with cognitive impairment in melanoma patients. Ann. Oncol. 30, 823–829 (2019). Among the first reports on neuronal auto-antibodies as possible biomarkers in the development of cancer-related cognitive impairment.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ruark, J. et al. Patient-reported neuropsychiatric outcomes of long-term survivors after chimeric antigen receptor T cell therapy. Biol. Blood Marrow Transpl. 26, 34–43 (2020).

    Google Scholar 

  19. Olson, B. & Marks, D. L. Pretreatment cancer-related cognitive impairment-mechanisms and outlook. Cancers 11, 687 (2019).

    CAS  PubMed Central  Google Scholar 

  20. van der Willik, K. D. et al. Trajectories of cognitive function prior to cancer diagnosis: a population-based study. J. Natl. Cancer Inst. 112, 480–488 (2020).

    PubMed  Google Scholar 

  21. DeVita, V. T. Jr & Chu, E. A history of cancer chemotherapy. Cancer Res. 68, 8643–8653 (2008).

    CAS  PubMed  Google Scholar 

  22. Cardoso, F. et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann. Oncol. 31, 1623–1649 (2020).

    CAS  PubMed  Google Scholar 

  23. Hanna, N. H. et al. Therapy for Stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J. Clin. Oncol. 38, 1608–1632 (2020).

    PubMed  Google Scholar 

  24. DeSantis, C. E. et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J. Clin. 64, 252–271 (2014).

    PubMed  Google Scholar 

  25. Andre, F. et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline update-integration of results from TAILORx. J. Clin. Oncol. 37, 1956–1964 (2019).

    CAS  PubMed  Google Scholar 

  26. Kris, M. G. et al. Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non-small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update. J. Clin. Oncol. 35, 2960–2974 (2017).

    PubMed  Google Scholar 

  27. Dietrich, J., Han, R., Yang, Y., Mayer-Pröschel, M. & Noble, M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J. Biol. 5, 22 (2006).

    PubMed  PubMed Central  Google Scholar 

  28. Delou, J. M. A., Souza, A. S. O., Souza, L. C. M. & Borges, H. L. Highlights in resistance mechanism pathways for combination therapy. Cells 8, 1013 (2019).

    CAS  PubMed Central  Google Scholar 

  29. Lange, M. et al. Baseline cognitive functions among elderly patients with localised breast cancer. Eur. J. Cancer 50, 2181–2189 (2014).

    PubMed  Google Scholar 

  30. Wefel, J. S., Lenzi, R., Theriault, R. L., Davis, R. N. & Meyers, C. A. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 100, 2292–2299 (2004).

    CAS  PubMed  Google Scholar 

  31. Wefel, J. S., Saleeba, A. K., Buzdar, A. U. & Meyers, C. A. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer 116, 3348–3356 (2010).

    PubMed  Google Scholar 

  32. Wefel, J. S., Kesler, S. R., Noll, K. R. & Schagen, S. B. Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA Cancer J. Clin. 65, 123–138 (2015).

    PubMed  Google Scholar 

  33. Janelsins, M. C. et al. Longitudinal trajectory and characterization of cancer-related cognitive impairment in a nationwide cohort study. J. Clin. Oncol. 36, Jco2018786624 (2018).

    Google Scholar 

  34. Koppelmans, V. et al. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J. Clin. Oncol. 30, 1080–1086 (2012). One of the few studies on very late cognitive effects of chemotherapy.

    PubMed  Google Scholar 

  35. Wefel, J. S. & Schagen, S. B. Chemotherapy-related cognitive dysfunction. Curr. Neurol. Neurosci. Rep. 12, 267–275 (2012).

    CAS  PubMed  Google Scholar 

  36. Boykoff, N., Moieni, M. & Subramanian, S. K. Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. J. Cancer Surviv. 3, 223–232 (2009).

    PubMed  PubMed Central  Google Scholar 

  37. Von Ah, D. et al. Cancer, cognitive impairment, and work-related outcomes: an integrative review. Oncol. Nurs. Forum 43, 602–616 (2016).

    PubMed  Google Scholar 

  38. van Dam, F. S. 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. 90, 210–218 (1998).

    PubMed  Google Scholar 

  39. Schagen, S. B., Hamburger, H. L., Muller, M. J., Boogerd, W. & van Dam, F. S. Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function. J. Neurooncol. 51, 159–165 (2001).

    CAS  PubMed  Google Scholar 

  40. Stouten-Kemperman, M. M. et al. Neurotoxicity in breast cancer survivors ≥10 years post-treatment is dependent on treatment type. Brain Imaging Behav. 9, 275–284 (2015).

    PubMed  Google Scholar 

  41. Collins, B., MacKenzie, J., Tasca, G. A., Scherling, C. & Smith, A. Cognitive effects of chemotherapy in breast cancer patients: a dose-response study. Psychooncology 22, 1517–1527 (2013). The first and only study that evaluated cognition after each course of chemotherapy.

    PubMed  Google Scholar 

  42. Hutchinson, A. D., Hosking, J. R., Kichenadasse, G., Mattiske, J. K. & Wilson, C. Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat. Rev. 38, 926–934 (2012).

    PubMed  Google Scholar 

  43. Gutenkunst, S. L., Vardy, J. L., Dhillon, H. M. & Bell, M. L. Correlates of cognitive impairment in adult cancer survivors who have received chemotherapy and report cognitive problems. Support. Care Cancer 29, 1377–1386 (2021).

    PubMed  Google Scholar 

  44. Boscher, C. et al. Perceived cognitive impairment in breast cancer survivors and its relationships with psychological factors. Cancers 12, 3000 (2020).

    CAS  PubMed Central  Google Scholar 

  45. Li, M. & Caeyenberghs, K. Longitudinal assessment of chemotherapy-induced changes in brain and cognitive functioning: a systematic review. Neurosci. Biobehav. Rev. 92, 304–317 (2018).

    PubMed  Google Scholar 

  46. de Ruiter, M. B. et al. Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging. Hum. Brain Mapp. 33, 2971–2983 (2012).

    PubMed  Google Scholar 

  47. Deprez, S. et al. Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum. Brain Mapp. 32, 480–493 (2011).

    PubMed  Google Scholar 

  48. Kesler, S. R. et al. Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls. Proc. Natl Acad. Sci. USA 110, 11600–11605 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Miao, H. et al. Functional connectivity change of brain default mode network in breast cancer patients after chemotherapy. Neuroradiology 58, 921–928 (2016).

    PubMed  Google Scholar 

  50. Zhang, Y. et al. Chemotherapy-induced functional changes of the default mode network in patients with lung cancer. Brain Imaging Behav. 14, 847–856 (2020).

    PubMed  Google Scholar 

  51. Kubli, S. P., Berger, T., Araujo, D. V., Siu, L. L. & Mak, T. W. Beyond immune checkpoint blockade: emerging immunological strategies. Nat. Rev. Drug Discov. 20, 899–919 (2021).

    CAS  PubMed  Google Scholar 

  52. Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019).

    CAS  PubMed  Google Scholar 

  55. Zimmer, L. et al. Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 395, 1558–1568 (2020).

    CAS  PubMed  Google Scholar 

  56. Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

    CAS  PubMed  Google Scholar 

  57. Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Balar, A. V. et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 1483–1492 (2017).

    CAS  PubMed  Google Scholar 

  59. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    CAS  PubMed  Google Scholar 

  60. Maus, M. V. et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events. J. Immunother. Cancer 8, e001511 (2020).

    PubMed  PubMed Central  Google Scholar 

  61. Cuzzubbo, S. et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur. J. Cancer 73, 1–8 (2017).

    CAS  PubMed  Google Scholar 

  62. McGinnis, G. J. et al. Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model. Oncotarget 8, 9155–9173 (2017).

    PubMed  Google Scholar 

  63. Rogiers, A. et al. Health-related quality of life, emotional burden, and neurocognitive function in the first generation of metastatic melanoma survivors treated with pembrolizumab: a longitudinal pilot study. Support. Care Cancer 28, 3267–3278 (2020). One of the first studies on the potential cognitive effects of immunotherapy.

    CAS  PubMed  Google Scholar 

  64. Rogiers, A. et al. Neurocognitive function, psychosocial outcome, and health-related quality of life of the first-generation metastatic melanoma survivors treated with ipilimumab. J. Immunol. Res. 2020, 2192480 (2020).

    PubMed  PubMed Central  Google Scholar 

  65. Brudno, J. N. & Kochenderfer, J. N. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 34, 45–55 (2019).

    CAS  PubMed  Google Scholar 

  66. Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Park, J. H. et al. Long-Term Follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Patterson, J. D., Henson, J. C., Breese, R. O., Bielamowicz, K. J. & Rodriguez, A. CAR T cell therapy for pediatric brain tumors. Front. Oncol. 10, 1582 (2020).

    PubMed  PubMed Central  Google Scholar 

  69. Neelapu, S. S. Managing the toxicities of CAR T-cell therapy. Hematol. Oncol. 37 (Suppl. 1), 48–52 (2019).

    CAS  PubMed  Google Scholar 

  70. Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transpl. 25, 625–638 (2019).

    CAS  Google Scholar 

  72. Gust, J. et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T Cells. Cancer Discov. 7, 1404–1419 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Santomasso, B. D. et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 8, 958–971 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Shalabi, H. et al. Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells. Nat. Rev. Clin. Oncol. 18, 363–378 (2021).

    PubMed  PubMed Central  Google Scholar 

  75. Belin, C. et al. Description of neurotoxicity in a series of patients treated with CAR T-cell therapy. Sci. Rep. 10, 18997 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Amidi, A. 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. 11, 769–783 (2017).

    PubMed  Google Scholar 

  77. Small, B. J. et al. Catechol-O-methyltransferase genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors. Cancer 117, 1369–1376 (2011).

    CAS  PubMed  Google Scholar 

  78. Buskbjerg, C. D. R., Amidi, A., Demontis, D., Nissen, E. R. & Zachariae, R. Genetic risk factors for cancer-related cognitive impairment: a systematic review. Acta Oncol. 58, 537–547 (2019).

    CAS  PubMed  Google Scholar 

  79. Sharafeldin, N. et al. Clinical and genetic risk prediction of cognitive impairment after blood or marrow transplantation for hematologic malignancy. J. Clin. Oncol. 38, 1312–1321 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Vega, J. N., Dumas, J. & Newhouse, P. A. Cognitive effects of chemotherapy and cancer-related treatments in older adults. Am. J. Geriatr. Psychiatry 25, 1415–1426 (2017).

    PubMed  PubMed Central  Google Scholar 

  81. Fernandez, H. R., Varma, A., Flowers, S. A. & Rebeck, G. W. Cancer chemotherapy related cognitive impairment and the impact of the Alzheimer’s disease risk factor APOE. Cancers 12, 3842 (2020).

    CAS  PubMed Central  Google Scholar 

  82. Moruno Manchon, J. F. et al. Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons. Sci. Rep. 6, 25705 (2016).

    Google Scholar 

  83. Torre, M., Dey, A., Woods, J. K. & Feany, M. B. Elevated oxidative stress and DNA damage in cortical neurons of chemotherapy patients. J. Neuropathol. Exp. Neurol. 80, 705–712 (2021).

    PubMed  PubMed Central  Google Scholar 

  84. Makarevich, O. et al. Mithramycin selectively attenuates DNA-damage-induced neuronal cell death. Cell Death Dis. 11, 587 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Alhareeri, A. A. et al. Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study. Breast Cancer Res. 22, 137 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Moruno-Manchon, J. F. et al. TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin. Aging 8, 3507–3519 (2016).

    PubMed  PubMed Central  Google Scholar 

  87. Wardill, H. R. et al. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. Int. J. Cancer 139, 2635–2645 (2016).

    CAS  PubMed  Google Scholar 

  88. von Kobbe, C. Targeting senescent cells: approaches, opportunities, challenges. Aging 11, 12844–12861 (2019). Introduction to cellular senescence in the treatment of ageing-related diseases, including cancer-related cognitive impairment.

    Google Scholar 

  89. Mignone, R. G. & Weber, E. T. Potent inhibition of cell proliferation in the hippocampal dentate gyrus of mice by the chemotherapeutic drug thioTEPA. Brain Res. 1111, 26–29 (2006).

    CAS  PubMed  Google Scholar 

  90. Seigers, R. et al. Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav. Brain Res. 186, 168–175 (2008).

    CAS  PubMed  Google Scholar 

  91. Licht, T. et al. Hippocampal neural stem cells facilitate access from circulation via apical cytoplasmic processes. eLife 9, e52134 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Monje, M. L. et al. Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann. Neurol. 62, 515–520 (2007).

    PubMed  Google Scholar 

  93. Subramaniam, C. B. et al. The microbiota-gut-brain axis: an emerging therapeutic target in chemotherapy-induced cognitive impairment. Neurosci. Biobehav. Rev. 116, 470–479 (2020).

    CAS  PubMed  Google Scholar 

  94. Andres, A. L., Gong, X., Di, K. & Bota, D. A. Low-doses of cisplatin injure hippocampal synapses: a mechanism for ‘chemo’ brain? Exp. Neurol. 255, 137–144 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Chiang, A. C. A., Huo, X., Kavelaars, A. & Heijnen, C. J. Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment. Brain Behav. Immun. 79, 319–325 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu, R. Y., Zhang, Y., Coughlin, B. L., Cleary, L. J. & Byrne, J. H. Doxorubicin attenuates serotonin-induced long-term synaptic facilitation by phosphorylation of p38 mitogen-activated protein kinase. J. Neurosci. 34, 13289–13300 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Huo, X., Reyes, T. M., Heijnen, C. J. & Kavelaars, A. Cisplatin treatment induces attention deficits and impairs synaptic integrity in the prefrontal cortex in mice. Sci. Rep. 8, 17400 (2018).

    PubMed  PubMed Central  Google Scholar 

  98. Cole, P. D. et al. Memantine protects rats treated with intrathecal methotrexate from developing spatial memory deficits. Clin. Cancer Res. 19, 4446–4454 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Vijayanathan, V., Gulinello, M., Ali, N. & Cole, P. D. Persistent cognitive deficits, induced by intrathecal methotrexate, are associated with elevated CSF concentrations of excitotoxic glutamate analogs and can be reversed by an NMDA antagonist. Behav. Brain Res. 225, 491–497 (2011).

    CAS  PubMed  Google Scholar 

  100. Karschnia, P., Parsons, M. W. & Dietrich, J. Pharmacologic management of cognitive impairment induced by cancer therapy. Lancet Oncol. 20, e92–e102 (2019).

    PubMed  Google Scholar 

  101. Li, G. M. Mechanisms and functions of DNA mismatch repair. Cell Res. 18, 85–98 (2008).

    CAS  PubMed  Google Scholar 

  102. Zell, J., Rota Sperti, F., Britton, S. & Monchaud, D. DNA folds threaten genetic stability and can be leveraged for chemotherapy. RSC Chem. Biol. 2, 47–76 (2021).

    CAS  PubMed  Google Scholar 

  103. Maynard, S., Fang, E. F., Scheibye-Knudsen, M., Croteau, D. L. & Bohr, V. A. DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb. Perspect. Med. 5, a025130 (2015).

    PubMed  PubMed Central  Google Scholar 

  104. Madabhushi, R., Pan, L. & Tsai, L. H. DNA damage and its links to neurodegeneration. Neuron 83, 266–282 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Bagnall-Moreau, C., Chaudhry, S., Salas-Ramirez, K., Ahles, T. & Hubbard, K. Chemotherapy-induced cognitive impairment is associated with increased inflammation and oxidative damage in the hippocampus. Mol. Neurobiol. 56, 7159–7172 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Heck, J. E., Albert, S. M., Franco, R. & Gorin, S. S. Patterns of dementia diagnosis in surveillance, epidemiology, and end results breast cancer survivors who use chemotherapy. J. Am. Geriatr. Soc. 56, 1687–1692 (2008).

    PubMed  Google Scholar 

  107. Wyld, L. et al. Senescence and cancer: a review of clinical implications of senescence and senotherapies. Cancers 12, 2134 (2020).

    CAS  PubMed Central  Google Scholar 

  108. Yang, H. et al. The role of cellular reactive oxygen species in cancer chemotherapy. J. Exp. Clin. Cancer Res. 37, 266 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Dominic, A., Hamilton, D. & Abe, J. I. Mitochondria and chronic effects of cancer therapeutics: the clinical implications. J. Thromb. Thrombolysis 51, 884–889 (2020).

    PubMed  PubMed Central  Google Scholar 

  110. Moruno-Manchon, J. F. et al. Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy. Mol. Cell. Neurosci. 86, 65–71 (2018).

    CAS  PubMed  Google Scholar 

  111. Golubev, A., Hanson, A. D. & Gladyshev, V. N. A tale of two concepts: harmonizing the free radical and antagonistic pleiotropy theories of aging. Antioxid. Redox Signal. 29, 1003–1017 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Gaman, A. M., Uzoni, A., Popa-Wagner, A., Andrei, A. & Petcu, E. B. The role of oxidative stress in etiopathogenesis of chemotherapy induced cognitive impairment (CICI)-“Chemobrain”. Aging Dis. 7, 307–317 (2016).

    PubMed  PubMed Central  Google Scholar 

  113. Gong, S. et al. Gut microbiota accelerates cisplatin-induced acute liver injury associated with robust inflammation and oxidative stress in mice. J. Transl. Med. 19, 147 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Konsman, J. P. et al. Translationally relevant mouse model of early life cancer and chemotherapy exposure results in brain and small intestine cytokine responses: a potential link to cognitive deficits. Brain Behav. Immun. 99, 192–202 (2021).

    PubMed  Google Scholar 

  115. Gibson, E. M. et al. Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell 176, 43–55.e13 (2019). Thorough evaluation of mechanisms underlying chemotherapy-induced cognitive impairment.

    CAS  PubMed  Google Scholar 

  116. Wang, B. et al. KIAA1522 potentiates TNFα-NFκB signaling to antagonize platinum-based chemotherapy in lung adenocarcinoma. J. Exp. Clin. Cancer Res. 39, 170 (2020).

    PubMed  PubMed Central  Google Scholar 

  117. Montagne A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bauer, M. et al. Impaired clearance from the brain increases the brain exposure to metoclopramide in elderly subjects. Clin. Pharmacol. Ther. 109, 754–761 (2021).

    CAS  PubMed  Google Scholar 

  119. Pluvinage, J. V. & Wyss-Coray, T. Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration. Nat. Rev. Neurosci. 21, 93–102 (2020).

    CAS  PubMed  Google Scholar 

  120. Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Williams, A. M. et al. Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy. J. Neuroimmunol. 314, 17–23 (2018).

    CAS  PubMed  Google Scholar 

  122. Carneiro-Filho, B. A. et al. Intestinal barrier function and secretion in methotrexate-induced rat intestinal mucositis. Dig. Dis. Sci. 49, 65–72 (2004).

    CAS  PubMed  Google Scholar 

  123. Honarpisheh, P. & McCullough, L. D. Sex as a biological variable in the pathology and pharmacology of neurodegenerative and neurovascular diseases. Br. J. Pharmacol. 176, 4173–4192 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Griesbeck, M. et al. Sex differences in plasmacytoid dendritic cell levels of IRF5 drive higher IFN-α production in women. J. Immunol. 195, 5327–5336 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Battram, A. M., Bachiller, M. & Martín-Antonio, B. Senescence in the development and response to cancer with immunotherapy: a double-edged sword. Int. J. Mol. Sci. 21, 4346 (2020).

    CAS  PubMed Central  Google Scholar 

  126. Wang, B., Kohli, J. & Demaria, M. Senescent cells in cancer therapy: friends or foes? Trends Cancer 6, 838–857 (2020).

    CAS  PubMed  Google Scholar 

  127. Csipo, T., Lipecz, A., Ashpole, N. M., Balasubramanian, P. & Tarantini, S. Astrocyte senescence contributes to cognitive decline. Geroscience 42, 51–55 (2020).

    PubMed  Google Scholar 

  128. Kapasi, A. & Schneider, J. A. Vascular contributions to cognitive impairment, clinical Alzheimer’s disease, and dementia in older persons. Biochim. Biophys. Acta 1862, 878–886 (2016).

    CAS  PubMed  Google Scholar 

  129. Koh, Y. Q. et al. Role of exosomes in cancer-related cognitive impairment. Int. J. Mol. Sci. 21, 2755 (2020).

    CAS  PubMed Central  Google Scholar 

  130. Goldberg, S. B. et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 17, 976–983 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Yshii, L. M., Hohlfeld, R. & Liblau, R. S. Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives. Nat. Rev. Neurol. 13, 755–763 (2017).

    CAS  PubMed  Google Scholar 

  132. Graus, F. & Dalmau, J. Paraneoplastic neurological syndromes in the era of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 16, 535–548 (2019).

    CAS  PubMed  Google Scholar 

  133. Gill, A. et al. A case series of PD-1 inhibitor-associated paraneoplastic neurologic syndromes. J. Neuroimmunol. 334, 576980 (2019).

    CAS  PubMed  Google Scholar 

  134. Haanen, J. et al. Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy. Ann. Oncol. 31, 724–744 (2020).

    CAS  PubMed  Google Scholar 

  135. Iwama, S. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6, 230ra245 (2014).

    Google Scholar 

  136. Eggermont, A. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 16, 522–530 (2015).

    CAS  PubMed  Google Scholar 

  137. Lengacher, C. A. et al. Moderating effects of genetic polymorphisms on improvements in cognitive impairment in breast cancer survivors participating in a 6-week mindfulness-based stress reduction program. Biol. Res. Nurs. 17, 393–404 (2015).

    CAS  PubMed  Google Scholar 

  138. McGinnis, G. J. & Raber, J. CNS side effects of immune checkpoint inhibitors: preclinical models, genetics and multimodality therapy. Immunotherapy 9, 929–941 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Taraseviciute, A. et al. Chimeric antigen receptor T cell-mediated neurotoxicity in nonhuman primates. Cancer Discov. 8, 750–763 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748 (2018).

    CAS  PubMed  Google Scholar 

  141. Parker, K. R. et al. Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies. Cell 183, 126–142.e17 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Chan, E., Fogler, J. M. & Hammerness, P. G. Treatment of attention-deficit/hyperactivity disorder in adolescents: a systematic review. JAMA 315, 1997–2008 (2016).

    CAS  PubMed  Google Scholar 

  143. Hersey, M. et al. Psychostimulant use disorder, an unmet therapeutic goal: can modafinil narrow the gap? Front. Neurosci. 15, 656475 (2021).

    PubMed  PubMed Central  Google Scholar 

  144. Majdi, A., Kamari, F., Sadigh-Eteghad, S. & Gjedde, A. Molecular insights into memory-enhancing metabolites of nicotine in brain: a systematic review. Front. Neurosci. 12, 1002 (2018).

    PubMed  Google Scholar 

  145. Bertrand, D. & Terry, A. V. Jr The wonderland of neuronal nicotinic acetylcholine receptors. Biochem. Pharmacol. 151, 214–225 (2018).

    CAS  PubMed  Google Scholar 

  146. Lower, E. E. et al. Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. J. Pain. Symptom Manage 38, 650–662 (2009).

    CAS  PubMed  Google Scholar 

  147. Mar Fan, H. G. et al. A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support. Care Cancer 16, 577–583 (2008).

    PubMed  Google Scholar 

  148. Escalante, C. P. et al. A randomized, double-blind, 2-period, placebo-controlled crossover trial of a sustained-release methylphenidate in the treatment of fatigue in cancer patients. Cancer J. 20, 8–14 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Kohli, S. et al. The effect of modafinil on cognitive function in breast cancer survivors. Cancer 115, 2605–2616 (2009).

    CAS  PubMed  Google Scholar 

  150. Berenson, J. R. et al. A phase 3 trial of armodafinil for the treatment of cancer-related fatigue for patients with multiple myeloma. Support. Care Cancer 23, 1503–1512 (2015).

    PubMed  Google Scholar 

  151. Lundorff, L. E., Jønsson, B. H. & Sjøgren, P. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial. Palliat. Med. 23, 731–738 (2009).

    CAS  PubMed  Google Scholar 

  152. Vega, J. N., Albert, K. M., Mayer, I. A., Taylor, W. D. & Newhouse, P. A. Nicotinic treatment of post-chemotherapy subjective cognitive impairment: a pilot study. J. Cancer Surviv. 13, 673–686 (2019).

    PubMed  PubMed Central  Google Scholar 

  153. Miladi, N., Dossa, R., Dogba, M. J., Cléophat-Jolicoeur, M. I. F. & Gagnon, B. Psychostimulants for cancer-related cognitive impairment in adult cancer survivors: a systematic review and meta-analysis. Support. Care Cancer 27, 3717–3727 (2019).

    PubMed  Google Scholar 

  154. Stojanoski, B., Wild, C. J., Battista, M. E., Nichols, E. S. & Owen, A. M. Brain training habits are not associated with generalized benefits to cognition: An online study of over 1000 “brain trainers”. J. Exp. Psychol. Gen. 150, 729–738 (2020).

    PubMed  Google Scholar 

  155. Simons, D. J. et al. Do “brain-training” programs work? Psychol. Sci. Public Interest. 17, 103–186 (2016).

    PubMed  Google Scholar 

  156. Winocur, G., Wojtowicz, J. M., Merkley, C. M. & Tannock, I. F. Environmental enrichment protects against cognitive impairment following chemotherapy in an animal model. Behav. Neurosci. 130, 428–436 (2016).

    PubMed  Google Scholar 

  157. Kesler, S. et al. Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors. Clin. Breast Cancer 13, 299–306 (2013).

    PubMed  PubMed Central  Google Scholar 

  158. Bray, V. J. et al. Evaluation of a web-based cognitive rehabilitation program in cancer survivors reporting cognitive symptoms after chemotherapy. J. Clin. Oncol. 35, 217–225 (2017).

    PubMed  Google Scholar 

  159. Poppelreuter, M., Weis, J., Mumm, A., Orth, H. B. & Bartsch, H. H. Rehabilitation of therapy-related cognitive deficits in patients after hematopoietic stem cell transplantation. Bone Marrow Transpl. 41, 79–90 (2008).

    CAS  Google Scholar 

  160. Mayo, S. J. et al. Computerized cognitive training in post-treatment hematological cancer survivors: a feasibility study. Pilot. Feasibility Stud. 7, 36 (2021).

    PubMed  PubMed Central  Google Scholar 

  161. Dos Santos, M. et al. Cognitive rehabilitation program to improve cognition of cancer patients treated with chemotherapy: a 3-arm randomized trial. Cancer 126, 5328–5336 (2020).

    PubMed  Google Scholar 

  162. Nguyen, L., Murphy, K. & Andrews, G. A game a day keeps cognitive decline away? A systematic review and meta-analysis of commercially-available brain training programs in healthy and cognitively impaired older adults. Neuropsychol. Rev. https://doi.org/10.1007/s11065-021-09515-2 (2021). Important review on current (lack of) efficacy evidence for brain training programmes.

    Article  PubMed  Google Scholar 

  163. Wilson, B. A. Towards a comprehensive model of cognitive rehabilitation. Neuropsychol. Rehabil. 12, 97–110 (2002).

    Google Scholar 

  164. Von Ah, D. & Crouch, A. Cognitive rehabilitation for cognitive dysfunction after cancer and cancer treatment: implications for nursing practice. Semin. Oncol. Nurs. 36, 150977 (2020).

    Google Scholar 

  165. Ferguson, R. J. et al. Cognitive-behavioral management of chemotherapy-related cognitive change. Psychooncology 16, 772–777 (2007). The first investigation into behavioural interventions for cognitive problems after chemotherapy.

    PubMed  PubMed Central  Google Scholar 

  166. Abraham, E. H., Khan, B., Ling, E. & Bernstein, L. J. The development and evaluation of a patient educational resource for cancer-related cognitive dysfunction. J. Cancer Educ. https://doi.org/10.1007/s13187-020-01793-3 (2020).

    Article  Google Scholar 

  167. Bernstein, L. J., McCreath, G. A., Nyhof-Young, J., Dissanayake, D. & Rich, J. B. A brief psychoeducational intervention improves memory contentment in breast cancer survivors with cognitive concerns: results of a single-arm prospective study. Support. Care Cancer 26, 2851–2859 (2018).

    PubMed  Google Scholar 

  168. Cherrier, M. M. et al. A randomized trial of cognitive rehabilitation in cancer survivors. Life Sci. 93, 617–622 (2013).

    CAS  PubMed  Google Scholar 

  169. Lawrence, J. A. et al. A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy. J. Cancer Surviv. 10, 176–184 (2016).

    CAS  PubMed  Google Scholar 

  170. Winocur, G. Chemotherapy and cognitive impairment: an animal model approach. Can. J. Exp. Psychol. 71, 265–273 (2017).

    PubMed  Google Scholar 

  171. Winocur, G., Binns, M. A. & Tannock, I. Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology 61, 1222–1228 (2011).

    CAS  PubMed  Google Scholar 

  172. Levy, M. J. F. et al. 5-HTT independent effects of fluoxetine on neuroplasticity. Sci. Rep. 9, 6311 (2019).

    PubMed  PubMed Central  Google Scholar 

  173. Mowla, A., Mosavinasab, M. & Pani, A. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J. Clin. Psychopharmacol. 27, 67–70 (2007).

    CAS  PubMed  Google Scholar 

  174. Prado, C. E., Watt, S. & Crowe, S. F. A meta-analysis of the effects of antidepressants on cognitive functioning in depressed and non-depressed samples. Neuropsychol. Rev. 28, 32–72 (2018).

    PubMed  Google Scholar 

  175. Kakehi, S. & Tompkins, D. M. A review of pharmacologic neurostimulant use during rehabilitation and recovery after brain injury. Ann. Pharmacother. 55, 1254–1266 (2021).

    PubMed  Google Scholar 

  176. Lyons, L., ElBeltagy, M., Bennett, G. & Wigmore, P. Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery. PLoS One 7, e30010 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01615055?term=NCT01615055&draw=2&rank=1 (2018).

  178. Wang, J. et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 11, 23–35 (2012).

    CAS  PubMed  Google Scholar 

  179. Ayoub, R. et al. Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin. Nat. Med. 26, 1285–1294 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Hartman, S. J. et al. The effects of weight loss and metformin on cognition among breast cancer survivors: evidence from the Reach for Health study. Psychooncology 28, 1640–1646 (2019).

    PubMed  PubMed Central  Google Scholar 

  181. Fabian, C. J., Kimler, B. F. & Hursting, S. D. Omega-3 fatty acids for breast cancer prevention and survivorship. Breast Cancer Res. 17, 62 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. Chang, A. et al. The anti-inflammatory drug aspirin does not protect against chemotherapy-induced memory impairment by paclitaxel in mice. Front. Oncol. 10, 564965 (2020).

    PubMed  PubMed Central  Google Scholar 

  183. Pavlock, S., McCarthy, D. M., Kesarwani, A., Jean-Pierre, P. & Bhide, P. G. Hippocampal neuroinflammation following combined exposure to cyclophosphamide and naproxen in ovariectomized mice. Int. J. Neurosci. https://doi.org/10.1080/00207454.2021.1896508 (2021).

    Article  PubMed  Google Scholar 

  184. Brown, T., Sykes, D. & Allen, A. R. Implications of breast cancer chemotherapy-induced inflammation on the gut, liver, and central nervous system. Biomedicines 9, 189 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Alexander, J. F. et al. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics 11, 3109–3130 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Salerno, E. A. et al. Physical activity patterns and relationships with cognitive function in patients with breast cancer before, during, and after chemotherapy in a prospective, nationwide study. J. Clin. Oncol. 39, 3283–3292 (2021).

    CAS  PubMed  Google Scholar 

  187. Rojer, A. G. M. et al. Objectively assessed physical activity and sedentary behavior and global cognitive function in older adults: a systematic review. Mech. Ageing Dev. 198, 111524 (2021).

    PubMed  Google Scholar 

  188. Fernández-Rodríguez, R. et al. Immediate effect of high-intensity exercise on brain-derived neurotrophic factor in healthy young adults: A systematic review and meta-analysis. J. Sport. Health Sci. https://doi.org/10.1016/j.jshs.2021.08.004 (2021).

    Article  PubMed  Google Scholar 

  189. Dauwan, M. et al. Physical exercise improves quality of life, depressive symptoms, and cognition across chronic brain disorders: a transdiagnostic systematic review and meta-analysis of randomized controlled trials. J. Neurol. 268, 1222–1246 (2021).

    PubMed  Google Scholar 

  190. Kennedy, G., Hardman, R. J., Macpherson, H., Scholey, A. B. & Pipingas, A. How does exercise reduce the rate of age-associated cognitive decline? A review of potential mechanisms. J. Alzheimers Dis. 55, 1–18 (2017).

    PubMed  Google Scholar 

  191. Campbell, K. L. et al. The effect of exercise on cancer-related cognitive impairment and applications for physical therapy: systematic review of randomized controlled trials. Phys. Ther. 100, 523–542 (2020).

    PubMed  PubMed Central  Google Scholar 

  192. Rosenberg, A., Mangialasche, F., Ngandu, T., Solomon, A. & Kivipelto, M. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from FINGER to World-Wide FINGERS. J. Prev. Alzheimers Dis. 7, 29–36 (2020).

    CAS  PubMed  Google Scholar 

  193. Kollins, S. H. et al. A novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a randomised controlled trial. Lancet Digit. Health 2, e168–e178 (2020).

    PubMed  Google Scholar 

  194. Noll, K. R., Bradshaw, M. E., Rexer, J. & Wefel, J. S. Neuropsychological practice in the oncology setting. Arch. Clin. Neuropsychol. 33, 344–353 (2018).

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, Netherlands

    Sanne B. Schagen

  2. Department of Psychology, University of Amsterdam, Amsterdam, Netherlands

    Sanne B. Schagen

  3. Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX, USA

    Andrey S. Tsvetkov

  4. UTHealth Consortium on Aging, The University of Texas McGovern Medical School at Houston, Houston, TX, USA

    Andrey S. Tsvetkov

  5. Department of Neuro-Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands

    Annette Compter

  6. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jeffrey S. Wefel

  7. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jeffrey S. Wefel

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S.B.S., A.S.T. and A.C. declare no competing interests as defined by Nature Research, or other interests that might be perceived to influence the interpretation of the article. J.S.W. declares the following research funding, unrelated to the preparation of this manuscript: Bayer, GT Medical Technology, Juno, Novocure, Roche, Vanquish Oncology.

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Netherlands Cancer Institute: https://www.avl.nl/voorbereiding-afspraak/afdelingen-en-centra/centrum-voor-kwaliteit-van-leven-ondersteunende-zorg/cognitieve-problemen-bij-kanker-en-kankerbehandeling/

Glossary

Neoadjuvant treatment

Therapy given before primary treatment.

Micrometastatic disease

Small numbers of cancer cells that have spread from the primary tumour to other parts of the body and are too few to be detected in a screening or diagnostic test.

DNA cross-linking agents

Chemotherapy agents that react with two nucleotides, forming a covalent linkage between them.

G-quadruplex-targeting drugs

Chemotherapy drugs that stabilize G-quadruplex DNA, resulting in DNA damage and altered gene expression.

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Schagen, S.B., Tsvetkov, A.S., Compter, A. et al. Cognitive adverse effects of chemotherapy and immunotherapy: are interventions within reach?. Nat Rev Neurol 18, 173–185 (2022). https://doi.org/10.1038/s41582-021-00617-2

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