Chemobrain: Mysteries and the importance of their revelation

Year 2022, Volume: 42 Issue: 4, 257 - 275, 01.12.2022

Meltem Tuncer

https://doi.org/10.52794/hujpharm.1100269

Abstract

Chemotherapy can be associated with both acute and delayed toxic effects on the central nervous system. Among the most commonly reported neurotoxic adverse effects in adult and pediatric cancer patients treated with chemotherapeutics are mood alterations and neurocognitive symptoms, such as disruption of memory, impaired attention, concentration, processing speed, and executive function. As a consequence of cancer therapy, these cognitive deficits that occur at any point during or following chemotherapy are called chemotherapy-related cognitive dysfunction or “chemobrain”. Notably, such symptoms can be progressive even after cessation of therapy and might significantly compromise the quality of life in affected patients who are unable to return to their prior social and academic level of performance. Trying to unpick the chemobrain’s pathophysiology has become a major challenge since patients undergoing chemotherapy have an increased risk of depression, anxiety, and other mood disorders, all of which can have a negative and interacting effect on cognitive function. The purpose of this review is to define and review what is known about this poorly understood phenomenon and unravel the mysteries of “chemobrain”, and summarize therapeutic avenues.

Keywords

chemotherapy, cognitive dysfunction, chemo-fog, central neurotoxicity, cancer

Kemobeyin: Gizemleri ve Açığa Çıkarılmasının Önemi

Abstract

Kemoterapi, merkezi sinir sisteminde hem akut hem de gecikmiş toksik etkilerle ilişkilendirilebilmektedir. Kemoterapötikler ile tedavi edilen yetişkin ve pediatrik kanser hastalarında en sık bildirilen nörotoksik yan etkiler arasında duygudurum değişiklikleri ve hafıza kaybı, dikkat eksikliği, odaklanmada zorluk, işlem hızı ve yürütme işlevindeki bozukluklar gibi nörobilişsel semptomlar yer almaktadır. Kanser tedavisinin bir sonucu olarak, kemoterapi sırasında veya sonrasında görülen bu bilişsel sorunlara kemoterapi ile ilişkili bilişsel işlev bozukluğu veya
“kemobeyin” denilmektedir. Bu tür semptomlar tedavinin kesilmesi sonrasında da ilerleyebilmekte ve önceki sosyal ve akademik performans seviyelerine geri dönemeyen hastalarda yaşam kalitesini önemli ölçüde bozabilmektedir. Kemoterapinin neden olduğu bilişsel işlev bozukluğunun patofizyolojisini açığa çıkarmak kolay değildir. Zira, tümü bilişsel işlev üzerinde olumsuz ve etkileşimli bir etkiye sahip olabilen depresyon, anksiyete ve diğer duygudurum bozuklukları kemobe- yine eşlik edebilmektedir. Bu derlemenin amacı, tam olarak anlaşılamayan kemobeyin hakkında bilinenleri tanımlamak, gözden geçirmek, bilinmeyenleri açığa çıkarmak ve mevcut tıbbi koşullar altındaki tedavi yaklaşımlarını özetlemektir.

Keywords

kemoterapi, bilişsel işlev bozukluğu, kemo bulanıklığı, merkezi nörotoksisite, kanser

References

• 1. Berger AM, Shuster JL, Von Roenn JH. Principles and practice of palliative care and supportive oncology: Lippincott Williams & Wilkins; 2007.
• 2. Ahles TA, Root JC, Ryan EL. Cancer-and cancer treatment–associated cognitive change: an update on the state of the science. Journal of Clinical Oncology. 2012;30(30):3675-86.
• 3. Ahles TA, Saykin AJ, McDonald BC, Furstenberg CT, Cole BF, Hanscom BS, et al. Cognitive function in breast cancer patients prior to adjuvant treatment. Breast cancer research and treatment. 2008;110(1):143-52.
• 4. Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA. ‘Chemobrain’in breast carcinoma? A prologue. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2004;101(3):466-75.
• 5. Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA. The cognitive sequelae of standard‐dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2004;100(11):2292-9.
• 6. Wefel JS, Saleeba AK, Buzdar AU, Meyers CA. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer. 2010;116(14):3348-56.
• 7. Silberfarb PM. Chemotherapy and cognitive defects in cancer patients. Annual review of medicine. 1983;34(1):35-46.
• 8. de Ruiter MB, Reneman L, Boogerd W, Veltman DJ, Van Dam FS, Nederveen AJ, et al. Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Human brain mapping. 2011;32(8):1206-19.
• 9. Heflin LH, Meyerowitz BE, Hall P, Lichtenstein P, Johansson B, Pedersen NL, et al. Cancer as a risk factor for long-term cognitive deficits and dementia. Journal of the National Cancer Institute. 2005;97(11):854-6.
• 10. Vardy J, Wefel J, Ahles T, Tannock I, Schagen S. Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Annals of Oncology. 2008;19(4):623-9.
• 11. Debess J, Riis JØ, Engebjerg MC, Ewertz M. Cognitive function after adjuvant treatment for early breast cancer: a population-based longitudinal study. Breast cancer research and treatment. 2010;121(1):91-100.
• 12. Donovan KA, Small BJ, Andrykowski MA, Schmitt FA, Munster P, Jacobsen PB. Cognitive functioning after adjuvant chemotherapy and/or radiotherapy for early‐stage breast carcinoma. Cancer: Interdisciplinary International Journal of the American Cancer Society. 2005;104(11):2499-507.
• 13. Jacqueline Galica R, Dale Rajacich R, Debbie Kane R. The impact of chemotherapy-induced cognitive impairment on the psychosocial adjustment of patients with nonmetastatic colorectal cancer. Clinical Journal of Oncology Nursing. 2012;16(2):163-9.
• 14. Hermelink K, Küchenhoff H, Untch M, Bauerfeind I, Lux MP, Bühner M, et al. Two different sides of ‘chemobrain’: determinants and nondeterminants of self‐perceived cognitive dysfunction in a prospective, randomized, multicenter study. Psycho‐oncology. 2010;19(12):1321-8.
• 15. Kurita K, Meyerowitz BE, Hall P, Gatz M. Long-term cognitive impairment in older adult twins discordant for gynecologic cancer treatment. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences. 2011;66(12):1343-9.
• 16. Tager FA, McKinley PS, Schnabel FR, El-Tamer M, Cheung YKK, Fang Y, et al. The cognitive effects of chemotherapy in post-menopausal breast cancer patients: a controlled longitudinal study. Breast cancer research and treatment. 2010;123(1):25-34.
• 17. Jansen CE, Miaskowski C, Dodd M, Dowling G. Chemotherapy-induced cognitive impairment in women with breast cancer: a critique of the literature. Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. 2005.
• 18. Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. Journal of Clinical Oncology. 2002;20(2):485-93.
• 19. van Dam FS, Boogerd W, Schagen SB, Muller MJ, Droogleever Fortuyn ME, Wall Ev, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. JNCI: Journal of the National Cancer Institute. 1998;90(3):210-8.
• 20. Mehnert A, Scherwath A, Schirmer L, Schleimer B, Petersen C, Schulz-Kindermann F, et al. The association between neuropsychological impairment, self-perceived cognitive deficits, fatigue and health related quality of life in breast cancer survivors following standard adjuvant versus high-dose chemotherapy. Patient Education and Counseling. 2007;66(1):108-18.
• 21. Poppelreuter M, Weis J, Külz A, Tucha O, Lange KW, Bartsch H. Cognitive dysfunction and subjective complaints of cancer patients: a cross-sectional study in a cancer rehabilitation centre. European Journal of Cancer. 2004;40(1):43-9.
• 22. Downie FP, Mar Fan HG, Houédé‐Tchen N, Yi Q, Tannock IF. Cognitive function, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: evaluation with patient interview after formal assessment. Psycho‐Oncology: Journal of the Psychological, Social and Behavioral Dimensions of Cancer. 2006;15(10):921-30.
• 23. Shilling V, Jenkins V, Morris R, Deutsch G, Bloomfield D. The effects of adjuvant chemotherapy on cognition in women with breast cancer—preliminary results of an observational longitudinal study. The Breast. 2005;14(2):142-50.
• 24. Reid‐Arndt SA, Hsieh C, Perry MC. Neuropsychological functioning and quality of life during the first year after completing chemotherapy for breast cancer. Psycho‐Oncology. 2010;19(5):535-44.
• 25. Fliessbach K, Helmstaedter C, Urbach H, Althaus A, Pels H, Linnebank M, et al. Neuropsychological outcome after chemotherapy for primary CNS lymphoma: a prospective study. Neurology. 2005;64(7):1184-8.
• 26. Weis J, Poppelreuter M, Bartsch H. Cognitive deficits as long‐term side‐effects of adjuvant therapy in breast cancer patients:‘Subjective’complaints and ‘objective’neuropsychological test results. Psycho‐Oncology: Journal of the Psychological, Social and Behavioral Dimensions of Cancer. 2009;18(7):775-82.
• 27. Poppelreuter M, Weis J, Bartsch H. Effects of specific neuropsychological training programs for breast cancer patients after adjuvant chemotherapy. Journal of psychosocial oncology. 2009;27(2):274-96.
• 28. Hutchinson AD, Hosking JR, Kichenadasse G, Mattiske JK, Wilson C. Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer treatment reviews. 2012;38(7):926-34.
• 29. Minton O, Stone PC. A comparison of cognitive function, sleep and activity levels in disease-free breast cancer patients with or without cancer-related fatigue syndrome. BMJ supportive & palliative care. 2012;2(3):231-8.
• 30. Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nature Reviews Cancer. 2007;7(3):192-201.
• 31. Bruno J, Hosseini SH, Kesler S. Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiology of disease. 2012;48(3):329-38.
• 32. Deprez S, Amant F, Yigit R, Porke K, Verhoeven J, Stock JVd, et al. Chemotherapy‐induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Human brain mapping. 2011;32(3):480-93.
• 33. McDonald BC, Conroy SK, Ahles TA, West JD, Saykin AJ. Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study. Journal of Clinical Oncology. 2012;30(20):2500-08.
• 34. Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, Akechi T, et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer. 2007;109(1):146-56.
• 35. Deprez S, Amant F, Smeets A, Peeters R, Leemans A, Van Hecke W, et al. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. Journal of Clinical Oncology. 2012;30(3):274-81.
• 36. Button KS, Ioannidis J, Mokrysz C, Nosek BA, Flint J, Robinson ES, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nature reviews neuroscience. 2013;14(5):365-76.
• 37. Hoeijmakers JH. DNA damage, aging, and cancer. New England Journal of Medicine. 2009;361(15):1475-85.
• 38. Maynard S, Fang EF, Scheibye-Knudsen M, Croteau DL, Bohr VA. DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harbor perspectives in medicine. 2015;5(10):a025130.
• 39. Mihlon F, Ray CE, Messersmith W, editors. Chemotherapy agents: a primer for the interventional radiologist. Seminars in interventional radiology; 2010: © Thieme Medical Publishers.
• 40. Dubey J, Ratnakaran N, Koushika SP. Neurodegeneration and microtubule dynamics: death by a thousand cuts. Frontiers in cellular neuroscience. 2015;9:343.
• 41. Pearson JN, Patel M. The role of oxidative stress in organophosphate and nerve agent toxicity. Annals of the New York Academy of Sciences. 2016;1378(1):17-24.
• 42. Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363-85.
• 43. Ming G-l, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011;70(4):687-702.
• 44. Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, et al. Neurogenesis in the striatum of the adult human brain. Cell. 2014;156(5):1072-83.
• 45. Choi R, Goldstein BJ. Olfactory epithelium: Cells, clinical disorders, and insights from an adult stem cell niche. Laryngoscope investigative otolaryngology. 2018;3(1):35-42.
• 46. Richardson RM, Sun D, Bullock MR. Neurogenesis after traumatic brain injury. Neurosurg Clin N Am. 2007;18(1):169-81, xi.
• 47. Shruster A, Melamed E, Offen D. Neurogenesis in the aged and neurodegenerative brain. Apoptosis. 2010;15(11):1415-21.
• 48. Nguyen LD, Ehrlich BE. Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases. EMBO molecular medicine. 2020;12(6):e12075.
• 49. Seigers R, Schagen SB, Beerling W, Boogerd W, Van Tellingen O, Van Dam FS, et al. Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behavioural brain research. 2008;186(2):168-75.
• 50. ELBeltagy M, Mustafa S, Umka J, Lyons L, Salman A, Tu C-YG, et al. Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behavioural brain research. 2010;208(1):112-7.
• 51. Briones TL, Woods J. Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC neuroscience. 2011;12(1):1-13.
• 52. Nokia MS, Anderson ML, Shors TJ. Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain. European Journal of Neuroscience. 2012;36(11):3521-30.
• 53. Mustafa S, Walker A, Bennett G, Wigmore PM. 5‐Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. European Journal of Neuroscience. 2008;28(2):323-30.
• 54. Christie L-A, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clinical cancer research. 2012;18(7):1954-65.
• 55. Jehn C, Becker B, Flath B, Nogai H, Vuong L, Schmid P, et al. Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression. Journal of neuroimmunology. 2015;287:88-92.
• 56. Zimmer P, Mierau A, Bloch W, Strüder HK, Hülsdünker T, Schenk A, et al. Post-chemotherapy cognitive impairment in patients with B-cell non-Hodgkin lymphoma: a first comprehensive approach to determine cognitive impairments after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone or rituximab and bendamustine. Leukemia & lymphoma. 2015;56(2):347-52.
• 57. Park H-S, Kim C-J, Kwak H-B, No M-H, Heo J-W, Kim T-W. Physical exercise prevents cognitive impairment by enhancing hippocampal neuroplasticity and mitochondrial function in doxorubicin-induced chemobrain. Neuropharmacology. 2018;133:451-61.
• 58. Geraghty AC, Gibson EM, Ghanem RA, Greene JJ, Ocampo A, Goldstein AK, et al. Loss of adaptive myelination contributes to methotrexate chemotherapy-related cognitive impairment. Neuron. 2019;103(2):250-65. e8.
• 59. 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. Journal of biology. 2006;5(7):1-23.
• 60. Han R, Yang YM, Dietrich J, Luebke A, Mayer-Pröschel M, Noble M. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. Journal of biology. 2008;7(4):1-22.
• 61. Zou YM, Lu D, Liu LP, Zhang HH, Zhou YY. Olfactory dysfunction in Alzheimer's disease. Neuropsychiatr Dis Treat. 2016;12:869-75.
• 62. Heck JE, Albert SM, Franco R, Gorin SS. Patterns of dementia diagnosis in surveillance, epidemiology, and end results breast cancer survivors who use chemotherapy. J Am Geriatr Soc. 2008;56(9):1687-92.
• 63. Kesler SR, Rao V, Ray WJ, Rao A, Initiative AsDN. Probability of Alzheimer's disease in breast cancer survivors based on gray-matter structural network efficiency. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2017;9:67-75.
• 64. Baxter NN, Durham SB, Phillips KA, Habermann EB, Virning BA. Risk of dementia in older breast cancer survivors: a population‐based cohort study of the association with adjuvant chemotherapy. Journal of the American Geriatrics Society. 2009;57(3):403-11.
• 65. Raji MA, Tamborello LP, Kuo Y-F, Ju H, Freeman JL, Zhang DD, et al. Risk of subsequent dementia diagnoses does not vary by types of adjuvant chemotherapy in older women with breast cancer. Medical oncology. 2009;26(4):452-9.
• 66. Barnes AP, Polleux F. Establishment of axon-dendrite polarity in developing neurons. Annual review of neuroscience. 2009;32:347-81.
• 67. Forrest MP, Parnell E, Penzes P. Dendritic structural plasticity and neuropsychiatric disease. Nature Reviews Neuroscience. 2018;19(4):215-34.
• 68. Dickstein DL, Weaver CM, Luebke JI, Hof PR. Dendritic spine changes associated with normal aging. Neuroscience. 2013;251:21-32.
• 69. Dorostkar MM, Zou C, Blazquez-Llorca L, Herms J. Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities. Acta neuropathologica. 2015;130(1):1-19.
• 70. Andres AL, Gong X, Di K, Bota DA. Low-doses of cisplatin injure hippocampal synapses: a mechanism for ‘chemo’brain? Experimental neurology. 2014;255:137-44.
• 71. Groves TR, Farris R, Anderson JE, Alexander TC, Kiffer F, Carter G, et al. 5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice. Behavioural brain research. 2017;316:215-24.
• 72. Acharya MM, Martirosian V, Chmielewski NN, Hanna N, Tran KK, Liao AC, et al. Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction. Cancer research. 2015;75(4):676-86.
• 73. Kang S, Lee S, Kim J, Kim J-C, Kim S-H, Son Y, et al. Chronic treatment with combined chemotherapeutic agents affects hippocampal micromorphometry and function in mice, independently of neuroinflammation. Experimental Neurobiology. 2018;27(5):419-436.
• 74. Zhou W, Kavelaars A, Heijnen CJ. Metformin Prevents Cisplatin-Induced Cognitive Impairment and Brain Damage in Mice. PLoS One. 2016;11(3):e0151890.
• 75. Graham WV, Bonito-Oliva A, Sakmar TP. Update on Alzheimer's disease therapy and prevention strategies. Annual review of medicine. 2017;68:413-30.
• 76. Naoi M, Maruyama W. Cell death of dopamine neurons in aging and Parkinson’s disease. Mechanisms of ageing and development. 1999;111(2-3):175-88.
• 77. Walker KR, Tesco G. Molecular mechanisms of cognitive dysfunction following traumatic brain injury. Frontiers in aging neuroscience. 2013;5:29.
• 78. Sheldrick A, Krug A, Markov V, Leube D, Michel T, Zerres K, et al. Effect of COMT val158met genotype on cognition and personality. European Psychiatry. 2008;23(6):385-9.
• 79. Small BJ, Rawson KS, Walsh E, Jim HS, Hughes TF, Iser L, et al. Catechol‐O‐methyltransferase genotype modulates cancer treatment‐related cognitive deficits in breast cancer survivors. Cancer. 2011;117(7):1369-76.
• 80. Cheng H, Li W, Gan C, Zhang B, Jia Q, Wang K. The COMT (rs165599) gene polymorphism contributes to chemotherapy-induced cognitive impairment in breast cancer patients. American journal of translational research. 2016;8(11):5087.
• 81. Thomas TC, Beitchman JA, Pomerleau F, Noel T, Jungsuwadee P, Butterfield DA, et al. Acute treatment with doxorubicin affects glutamate neurotransmission in the mouse frontal cortex and hippocampus. Brain Res. 2017;1672:10-7.
• 82. Kaplan SV, Limbocker RA, Gehringer RC, Divis JL, Osterhaus GL, Newby MD, et al. Impaired brain dopamine and serotonin release and uptake in wistar rats following treatment with carboplatin. ACS chemical neuroscience. 2016;7(6):689-99.
• 83. Jarmolowicz DP, Gehringer R, Lemley SM, Sofis MJ, Kaplan S, Johnson MA. 5-Fluorouracil impairs attention and dopamine release in rats. Behavioural brain research. 2019;362:319-22.
• 84. El-Agamy SE, Abdel-Aziz AK, Wahdan S, Esmat A, Azab SS. Astaxanthin ameliorates doxorubicin-induced cognitive impairment (chemobrain) in experimental rat model: impact on oxidative, inflammatory, and apoptotic machineries. Molecular neurobiology. 2018;55(7):5727-40.
• 85. Keeney JT, Ren X, Warrier G, Noel T, Powell DK, Brelsfoard JM, 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):30324-339.
• 86. Jessen KR. Glial cells. The international journal of biochemistry & cell biology. 2004;36(10):1861-7.
• 87. Fields RD, Araque A, Johansen-Berg H, Lim S-S, Lynch G, Nave K-A, et al. Glial biology in learning and cognition. The neuroscientist. 2014;20(5):426-31.
• 88. McDougall S, Riad WV, Silva-Gotay A, Tavares ER, Harpalani D, Li G-L, et al. Myelination of axons corresponds with faster transmission speed in the prefrontal cortex of developing male rats. eneuro. 2018;5(4):0203-18.
• 89. Bendlin BB, Fitzgerald ME, Ries ML, Xu G, Kastman EK, Thiel BW, et al. White matter in aging and cognition: a cross-sectional study of microstructure in adults aged eighteen to eighty-three. Developmental neuropsychology. 2010;35(3):257-77.
• 90. Lu PH, Lee GJ, Raven EP, Tingus K, Khoo T, Thompson PM, et al. Age-related slowing in cognitive processing speed is associated with myelin integrity in a very healthy elderly sample. Journal of clinical and experimental neuropsychology. 2011;33(10):1059-68.
• 91. McKenzie IA, Ohayon D, Li H, Paes de Faria J, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination. science. 2014;346(6207):318-22.
• 92. Steadman PE, Xia F, Ahmed M, Mocle AJ, Penning AR, Geraghty AC, et al. Disruption of oligodendrogenesis impairs memory consolidation in adult mice. Neuron. 2020;105(1):150-64. e6.
• 93. Chen BT, Ye N, Wong CW, Patel SK, Jin T, Sun C-L, et al. Effects of chemotherapy on aging white matter microstructure: a longitudinal diffusion tensor imaging study. Journal of geriatric oncology. 2020;11(2):290-6.
• 94. Hyrien O, Dietrich J, Noble M. Mathematical and experimental approaches to identify and predict the effects of chemotherapy on neuroglial precursors. Cancer research. 2010;70(24):10051-9.
• 95. Gibson EM, Nagaraja S, Ocampo A, Tam LT, Wood LS, Pallegar PN, et al. Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell. 2019;176(1-2):43-55. e13.
• 96. Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;81(2):229-48.
• 97. Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R. Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. Journal of neuroinflammation. 2018;15(1):1-26.
• 98. Lynch AM, Murphy KJ, Deighan BF, O'Reilly J-A, Gun'ko YK, Cowley TR, et al. The impact of glial activation in the aging brain. Aging and disease. 2010;1(3):262-78.
• 99. Seigers R, Timmermans J, van der Horn HJ, de Vries EF, Dierckx RA, Visser L, et al. Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behavioural brain research. 2010;207(2):265-72.
• 100. Fardell JE, Zhang J, De Souza R, Vardy J, Johnston I, Allen C, et al. The impact of sustained and intermittent docetaxel chemotherapy regimens on cognition and neural morphology in healthy mice. Psychopharmacology. 2014;231(5):841-52.
• 101. Alibhai JD, Diack AB, Manson JC. Unravelling the glial response in the pathogenesis of Alzheimer's disease. The FASEB Journal. 2018;32(11):5766-77.
• 102. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918-34.
• 103. Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, et al. Proinflammatory cytokines, aging, and age-related diseases. Journal of the American Medical Directors Association. 2013;14(12):877-82.
• 104. Wang X-M, Walitt B, Saligan L, Tiwari AF, Cheung CW, Zhang Z-J. Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine. 2015;72(1):86-96.
• 105. Ren X, Clair DKS, Butterfield DA. Dysregulation of cytokine mediated chemotherapy induced cognitive impairment. Pharmacological research. 2017;117:267-73.
• 106. Reale M, Greig N, Kamal M. Peripheral chemo-cytokine profiles in Alzheimer’s and Parkinson’s diseases. Mini reviews in medicinal chemistry. 2009;9(10):1229-41.
• 107. Sparkman NL, Johnson RW. Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation. 2008;15(4-6):323-30.
• 108. Di Benedetto S, Müller L, Wenger E, Düzel S, Pawelec G. Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neuroscience & Biobehavioral Reviews. 2017;75:114-28.
• 109. Remarque E, Bollen E, Weverling-Rijnsburger A, Laterveer J, Blauw G, Westendorp R. Patients with Alzheimer's disease display a pro-inflammatory phenotype. Experimental Gerontology. 2001;36(1):171-6.
• 110. Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer's disease. Biological psychiatry. 2010;68(10):930-41.
• 111. Caplan B, Bogner J, Brenner L, Kumar RG, Boles JA, Wagner AK. Chronic inflammation after severe traumatic brain injury: characterization and associations with outcome at 6 and 12 months postinjury. Journal of Head Trauma Rehabilitation. 2015;30(6):369-81.
• 112. Schimmel SJ, Acosta S, Lozano D. Neuroinflammation in traumatic brain injury: a chronic response to an acute injury. Brain circulation. 2017;3(3):135-42.
• 113. Guerreiro RJ, Santana I, Brás JM, Santiago B, Paiva A, Oliveira C. Peripheral inflammatory cytokines as biomarkers in Alzheimer’s disease and mild cognitive impairment. Neurodegenerative Diseases. 2007;4(6):406-12.
• 114. Gorska-Ciebiada M, Saryusz-Wolska M, Borkowska A, Ciebiada M, Loba J. Serum levels of inflammatory markers in depressed elderly patients with diabetes and mild cognitive impairment. PloS one. 2015;10(3):e0120433.
• 115. Chen X, Hu Y, Cao Z, Liu Q, Cheng Y. Cerebrospinal fluid inflammatory cytokine aberrations in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: a systematic review and meta-analysis. Frontiers in immunology. 2018:2122.
• 116. Shi D-D, Huang Y-H, Lai CSW, Dong CM, Ho LC, Wu EX, et al. Chemotherapy-induced cognitive impairment is associated with cytokine dysregulation and disruptions in neuroplasticity. Molecular neurobiology. 2019;56(3):2234-43.
• 117. Brandolini L, d’Angelo M, Antonosante A, Cimini A, Allegretti M. Chemokine signaling in chemotherapy-induced neuropathic pain. International journal of molecular sciences. 2019;20(12):2904.
• 118. Zhao Z, Pan X, Liu L, Liu N. Telomere length maintenance, shortening, and lengthening. Journal of cellular physiology. 2014;229(10):1323-9.
• 119. Schröder C, Wisman G, De Jong S, Van der Graaf W, Ruiters M, Mulder N, et al. Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation. British journal of cancer. 2001;84(10):1348-53.
• 120. Vasa-Nicotera M, Brouilette S, Mangino M, Thompson JR, Braund P, Clemitson J-R, et al. Mapping of a major locus that determines telomere length in humans. The American Journal of Human Genetics. 2005;76(1):147-51.
• 121. Sengupta S, Sobo M, Lee K, Kumar SS, White AR, Mender I, et al. Induced telomere damage to treat telomerase expressing therapy-resistant pediatric brain tumors. Molecular cancer therapeutics. 2018;17(7):1504-14.
• 122. Bolzán AD, Bianchi MS. DNA and chromosome damage induced by bleomycin in mammalian cells: An update. Mutation Research/Reviews in Mutation Research. 2018;775:51-62.
• 123. Flanary BE, Streit WJ. Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia. 2004;45(1):75-88.
• 124. Yuyama K, Igarashi Y. Physiological and pathological roles of exosomes in the nervous system. Biomolecular Concepts. 2016;7(1):53-68.
• 125. Ahles TA, Saykin AJ, McDonald BC, Li Y, Furstenberg CT, Hanscom BS, et al. Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. Journal of Clinical Oncology. 2010;28(29):4434-40.
• 126. Conroy SK, McDonald BC, Smith DJ, Moser LR, West JD, Kamendulis LM, 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 research and treatment. 2013;137(2):493-502.
• 127. Sepehry AA, Tyldesley S, Davis MK, Simmons C, Rauscher A, Lang DJ-M. RE: elucidating pretreatment cognitive impairment in breast cancer patients: the impact of cancer-related post-traumatic stress. JNCI: Journal of the National Cancer Institute. 2016;108(8):djw048.
• 128. Chiang AC, Huo X, Kavelaars A, Heijnen CJ. Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment. Brain, behavior, and immunity. 2019;79:319-25.
• 129. Mancuso A, Migliorino M, De Santis S, Saponiero A, De Marinis F. Correlation between anemia and functional/cognitive capacity in elderly lung cancer patients treated with chemotherapy. Annals of Oncology. 2006;17(1):146-50.
• 130. Horowitz TS, Suls J, Treviño M. A call for a neuroscience approach to cancer-related cognitive impairment. Trends in neurosciences. 2018;41(8):493-6.
• 131. Ferguson RJ, McDonald BC, Rocque MA, Furstenberg CT, Horrigan S, Ahles TA, et al. Development of CBT for chemotherapy‐related cognitive change: results of a waitlist control trial. Psycho‐Oncology. 2012;21(2):176-86.
• 132. Kesler S, Hosseini SH, Heckler C, Janelsins M, Palesh O, Mustian K, et al. Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors. Clinical breast cancer. 2013;13(4):299-306.
• 133. Henneghan AM, Harrison T. Complementary and alternative medicine therapies as symptom management strategies for the late effects of breast cancer treatment. Journal of Holistic Nursing. 2015;33(1):84-97.
• 134. Vance DE, Frank JS, Bail J, Triebel KL, Niccolai LM, Gerstenecker A, et al. Interventions for cognitive deficits in breast cancer survivors treated with chemotherapy. Cancer nursing. 2017;40(1):E11-E27.
• 135. Pangalos MN, Schechter LE, Hurko O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nature Reviews Drug Discovery. 2007;6(7):521-32.
• 136. Voss MW, Vivar C, Kramer AF, van Praag H. Bridging animal and human models of exercise-induced brain plasticity. Trends in cognitive sciences. 2013;17(10):525-44.
• 137. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H. When neurogenesis encounters aging and disease. Trends in neurosciences. 2010;33(12):569-79.
• 138. Bondi CO, Klitsch KC, Leary JB, Kline AE. Environmental enrichment as a viable neurorehabilitation strategy for experimental traumatic brain injury. Journal of neurotrauma. 2014;31(10):873-88.
• 139. Samuels BA, Hen R. Neurogenesis and affective disorders. European Journal of Neuroscience. 2011;33(6):1152-9.
• 140. Fardell JE, Vardy J, Shah JD, Johnston IN. Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity. Psychopharmacology. 2012;220(1):183-93.
• 141. Winocur G, Wojtowicz JM, Huang J, Tannock IF. Physical exercise prevents suppression of hippocampal neurogenesis and reduces cognitive impairment in chemotherapy-treated rats. Psychopharmacology. 2014;231(11):2311-20.
• 142. Winocur G, Wojtowicz JM, Merkley CM, Tannock IF. Environmental enrichment protects against cognitive impairment following chemotherapy in an animal model. Behavioral Neuroscience. 2016;130(4):428-36.
• 143. Lima Giacobbo B, Doorduin J, Klein HC, Dierckx RA, Bromberg E, de Vries EF. Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation. Molecular neurobiology. 2019;56(5):3295-312.
• 144. Schoenfeld TJ, Cameron HA. Adult neurogenesis and mental illness. Neuropsychopharmacology. 2015;40(1):113-28.
• 145. Shohayeb B, Diab M, Ahmed M, Ng DCH. Factors that influence adult neurogenesis as potential therapy. Translational neurodegeneration. 2018;7(1):1-19.
• 146. Young W. Review of lithium effects on brain and blood. Cell transplantation. 2009;18(9):951-75.
• 147. Lyons L, ElBeltagy M, Umka J, Markwick R, Startin C, Bennett G, et al. Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology. 2011;215(1):105-15.
• 148. 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. 2012;7(1):e30010.
• 149. Huehnchen P, Boehmerle W, Springer A, Freyer D, Endres M. A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice. Translational psychiatry. 2017;7(8):e1185-e.
• 150. Lindvall O, Kokaia Z. Stem cells in human neurodegenerative disorders—time for clinical translation? The Journal of clinical investigation. 2010;120(1):29-40.
• 151. Wang Z, Peng W, Zhang C, Sheng C, Huang W, Wang Y, et al. Effects of stem cell transplantation on cognitive decline in animal models of Alzheimer’s disease: a systematic review and meta-analysis. Scientific reports. 2015;5(1):1-10.
• 152. Vijayanathan V, Gulinello M, Ali N, Cole PD. 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. Behavioural brain research. 2011;225(2):491-7.
• 153. Cheng J, Liu X, Cao L, Zhang T, Li H, Lin W. Neo-adjuvant chemotherapy with cisplatin induces low expression of NMDA receptors and postoperative cognitive impairment. Neuroscience Letters. 2017;637:168-74.
• 154. Partin KM. AMPA receptor potentiators: from drug design to cognitive enhancement. Current opinion in pharmacology. 2015;20:46-53.
• 155. Phoumthipphavong V, Barthas F, Hassett S, Kwan AC. Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. Eneuro. 2016;3(2):1–14.
• 156. Duman RS. Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide. F1000Research. 2018;7.
• 157. Higley MJ, Sabatini BL. Calcium signaling in dendritic spines. Cold Spring Harbor perspectives in biology. 2012;4(4):a005686.
• 158. Arnsten AF. Stress weakens prefrontal networks: molecular insults to higher cognition. Nature neuroscience. 2015;18(10):1376-85.
• 159. Callaghan CK, O’Mara SM. Long-term cognitive dysfunction in the rat following docetaxel treatment is ameliorated by the phosphodiesterase-4 inhibitor, rolipram. Behavioural brain research. 2015;290:84-9.
• 160. Johnston IN, Tan M, Cao J, Matsos A, Forrest DR, Si E, et al. Ibudilast reduces oxaliplatin-induced tactile allodynia and cognitive impairments in rats. Behavioural Brain Research. 2017;334:109-18.
• 161. Hains AB, Vu MAT, Maciejewski PK, van Dyck CH, Gottron M, Arnsten AF. Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proceedings of the National Academy of Sciences. 2009;106(42):17957-62.
• 162. Brudvig JJ, Weimer JM. X MARCKS the spot: myristoylated alanine-rich C kinase substrate in neuronal function and disease. Frontiers in cellular neuroscience. 2015;9:407.
• 163. Noudoost B, Moore T. The role of neuromodulators in selective attention. Trends in cognitive sciences. 2011;15(12):585-91.
• 164. Winocur G, Binns MA, Tannock I. Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology. 2011;61(8):1222-8.
• 165. Lim I, Joung H-Y, Yu AR, Shim I, Kim JS. PET evidence of the effect of donepezil on cognitive performance in an animal model of chemobrain. BioMed research international. 2016;2016.
• 166. Heal D.J., Smith S.L., Findling R.L. (2011) ADHD: Current and Future Therapeutics. In: Stanford C., Tannock R. (eds) Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences, vol 9: 361-90. Springer, Berlin, Heidelberg.
• 167. Gong S, Sheng P, Jin H, He H, Qi E, Chen W, et al. Effect of methylphenidate in patients with cancer-related fatigue: a systematic review and meta-analysis. PloS one. 2014;9(1):e84391.
• 168. Cullum JL, Wojciechowski AE, Pelletier G, Simpson JSA. Bupropion sustained release treatment reduces fatigue in cancer patients. The Canadian Journal of Psychiatry. 2004;49(2):139-44.
• 169. Ozben T, Ozben S. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer's disease. Clinical biochemistry. 2019;72:87-9.
• 170. Gholamzad M, Ebtekar M, Ardestani MS, Azimi M, Mahmodi Z, Mousavi MJ, et al. A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflammation Research. 2019;68(1):25-38.
• 171. Dagher NN, Najafi AR, Kayala KMN, Elmore MR, White TE, Medeiros R, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. Journal of neuroinflammation. 2015;12(1):1-14.
• 172. Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell death & disease. 2013;4(3):e525-e.
• 173. Garwood CJ, Cooper JD, Hanger DP, Noble W. Anti-inflammatory impact of minocycline in a mouse model of tauopathy. Frontiers in psychiatry. 2010;1:136.
• 174. Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. Journal of neuroinflammation. 2012;9(1):1-16.
• 175. Yang M, Kim J-S, Kim J, Jang S, Kim S-H, Kim J-C, et al. Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer. Brain research bulletin. 2012;89(1-2):50-6.
• 176. Scott G, Zetterberg H, Jolly A, Cole JH, De Simoni S, Jenkins PO, et al. Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. Brain. 2018;141(2):459-71.
• 177. Howard R, Zubko O, Bradley R, Harper E, Pank L, O’brien J, et al. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial. JAMA neurology. 2020;77(2):164-74.
• 178. Matsos A, Loomes M, Zhou I, Macmillan E, Sabel I, Rotziokos E, et al. Chemotherapy-induced cognitive impairments: White matter pathologies. Cancer treatment reviews. 2017;61:6-14.
• 179. Ben-Hur T. Cell therapy for multiple sclerosis. Neurotherapeutics. 2011;8(4):625-42.
• 180. Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nature neuroscience. 2017;20(5):637-47.
• 181. Ahles TA, Saykin AJ, Noll WW, Furstenberg CT, Guerin S, Cole B, et al. The relationship of APOE genotype to neuropsychological performance in long‐term cancer survivors treated with standard dose chemotherapy. Psycho‐Oncology: Journal of the Psychological, Social and Behavioral Dimensions of Cancer. 2003;12(6):612-9.
• 182. Mandelblatt JS, Small BJ, Luta G, Hurria A, Jim H, McDonald BC, et al. Cancer-related cognitive outcomes among older breast cancer survivors in the thinking and living with cancer study. Journal of clinical oncology. 2018;36(32):3211-22.