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Treatment of Radiation-Induced Cognitive Decline in Adult Brain Tumor Patients

  • Christina K. CramerEmail author
  • Tiffany L. Cummings
  • Rachel N. Andrews
  • Roy Strowd
  • Stephen R. Rapp
  • Edward G. Shaw
  • Michael D. Chan
  • Glenn J. Lesser
Neuro-oncology (GJ Lesser, Section Editor)
  • 129 Downloads
Part of the following topical collections:
  1. Topical Collection on Neuro-oncology

Opinion statement

Patients with either primary or metastatic brain tumors quite often have cognitive impairment. Maintaining cognitive function is important to brain tumor patients and a decline in cognitive function is generally accompanied by a decline in functional independence and performance status. Cognitive decline can be a result of tumor progression, depression/anxiety, fatigue/sleep dysfunction, or the treatments they have received. It is our opinion that providers treating brain tumor patients should obtain pre-treatment and serial cognitive testing in their patients and offer mitigating and therapeutic interventions when appropriate. They should also support cognition-focused clinical trials.

Keywords

Cognition Brain Radiation Neuropsychology Memory Attention 

Notes

Compliance with Ethical Standards

Conflict of Interest

Christina K. Cramer has received speaker’s honoraria from Monteris Medical, and is also a member of teaching faculty for an on-site SBRT training course to which Elekta refers customers and for which Elekta reimburses the department.

Tiffany L. Cummings declares that she has no conflict of interest.

Rachel N. Andrews declares that she has no conflict of interest.

Michael Chan has received speaker’s honoraria from Monteris Medical, and is also a member of teaching faculty for an on-site SBRT training course to which Elekta refers customers and for which Elekta reimburses the department.

Roy Strowd declares that he has no conflict of interest.

Stephen R. Rapp declares that he has no conflict of interest.

Edward G. Shaw declares that he has no conflict of interest.

Glenn J. Lesser has received clinical trial support from Vascular Biogenics, Incyte, NewLink Genetics, Novartis, Immunocellular Therapeutics, and Pfizer; has received compensation from Monteris Medical and Insys Therapeutics for service as a consultant; and has received compensation from Stemline Therapeutics for serving as Data Safety and Monitoring Board Chair for a study.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Johnson DR, Sawyer AM, Meyers CA, O’Neill BP, Wefel JS. Early measures of cognitive function predict survival in patients with newly diagnosed glioblastoma. Neuro-Oncology. 2012;14(6):808–16.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: a review. Front Oncol. 2012;2:73.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Meyers CA, Smith JA, Bezjak A, Mehta MP, Liebmann J, Illidge T, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol. 2004;22(1):157–65.PubMedGoogle Scholar
  4. 4.
    •• Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncology. 2013;15(10):1429–37 This randomized, placebo-controlled study did not meet its pre-specified primary endpoint but did show that time to cognitive decline is longer in patients who receive memantine during and after WBRT.PubMedPubMedCentralGoogle Scholar
  5. 5.
    •• Rapp SR, Case LD, Peiffer A, Naughton MM, Chan MD, Stieber VW, et al. Donepezil for irradiated brain tumor survivors: a phase III randomized placebo-controlled clinical trial. J Clin Oncol. 2015;33(15):1653–9 This was a seminal randomized, phase III, open-label, placebo-controlled trial enrolled irradiated brain tumor survivors (at least 6 months after RT) and evaluated cognition before treatment with donepezil or placebo and then after 24 weeks of medication. This study did not meet its pre-specified primary endpoint but patients randomized to donepezil performed better on measures of verbal and working memory (HVLT-DR and -IR). There was also an interaction effect between pre-randomization (baseline) cognitive performance and treatment group—patients with poorer initial cognitive functioning benefited more from donepezil. For this reason, donepezil continues to be used in the clinic.PubMedPubMedCentralGoogle Scholar
  6. 6.
    • Butler JM Jr, Case LD, Atkins J, Frizzell B, Sanders G, Griffin P, et al. A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy. Int J Radiat Oncol Biol Phys. 2007;69(5):1496–501 This was a randomized, open-label, placebo-controlled phase III trial of methylphenidate taken during brain RT and for 8 weeks after, showed no difference fatigue or cognition between patients taking methylphenidate and those taking placebo. This study was hindered by a higher than expected drop-out rate which may have left it underpowered to detect a true difference. There are other smaller studies to support the use of methylphenidate in treating cancer-related fatigue which is why methylphenidate is still used clinically.PubMedGoogle Scholar
  7. 7.
    Attia A, Rapp SR, Case LD, D’Agostino R, Lesser G, Naughton M, et al. Phase II study of Ginkgo biloba in irradiated brain tumor patients: effect on cognitive function, quality of life, and mood. J Neuro-Oncol. 2012;109(2):357–63.Google Scholar
  8. 8.
    • Gehring K, Sitskoorn MM, Gundy CM, Sikkes SA, Klein M, Postma TJ, et al. Cognitive rehabilitation in patients with gliomas: a randomized, controlled trial. J Clin Oncol. 2009;27(22):3712–22 In this study, low-grade glioma survivors with stable disease were randomized to a cognitive rehabilitation program or the wait list. The program consisted 7 weeks of rehabilitation. Immediately after treatment, patients who participated in the rehabilitation program reported improved cognitive functioning on questionnaires but did not perform better on objective measures of cognitive performance. However, after 6 months, the patients who underwent rehabilitation performed objectively better on measures of verbal memory and attention compared to control patients and reported less mental fatigue.PubMedGoogle Scholar
  9. 9.
    Jenrow KA, Brown SL, Liu J, Kolozsvary A, Lapanowski K, Kim JH. Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus. Radiat Oncol. 2010;5:6.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Lee TC, Greene-Schloesser D, Payne V, Diz DI, Hsu FC, Kooshki M, et al. Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiat Res. 2012;178(1):46–56.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ramanan S, Kooshki M, Zhao W, Hsu FC, Riddle DR, Robbins ME. The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int J Radiat Oncol Biol Phys. 2009;75(3):870–7.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Liu JL, Tian DS, Li ZW, Qu WS, Zhan Y, Xie MJ, et al. Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo. Brain Res. 2010;1316:101–11.PubMedGoogle Scholar
  13. 13.
    Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302(5651):1760–5.PubMedGoogle Scholar
  14. 14.
    Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32(34):3810–6.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Begolly S, Olschowka JA, Love T, Williams JP, O’Banion MK. Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion. Glia. 2018;66(4):846–61.PubMedGoogle Scholar
  16. 16.
    Andrews RN, Metheny-Barlow LJ, Peiffer AM, Hanbury DB, Tooze JA, Bourland JD, et al. Cerebrovascular remodeling and neuroinflammation is a late effect of radiation-induced brain injury in non-human primates. Radiat Res. 2017.Google Scholar
  17. 17.
    Hanbury DB, Robbins ME, Bourland JD, Wheeler KT, Peiffer AM, Mitchell EL, et al. Pathology of fractionated whole-brain irradiation in rhesus monkeys ( Macaca mulatta ). Radiat Res. 2015.Google Scholar
  18. 18.
    Schultheiss TE, Kun LE, Ang KK, Stephens LC. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys. 1995;31(5):1093–112.PubMedGoogle Scholar
  19. 19.
    Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med. 2002;8(9):955–62.PubMedGoogle Scholar
  20. 20.
    Ungvari Z, Podlutsky A, Sosnowska D, Tucsek Z, Toth P, Deak F, et al. Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosensitivity. J Gerontol A Biol Sci Med Sci. 2013;68(12):1443–57.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Shirai K, Mizui T, Suzuki Y, Okamoto M, Hanamura K, Yoshida Y, et al. X irradiation changes dendritic spine morphology and density through reduction of cytoskeletal proteins in mature neurons. Radiat Res. 2013;179(6):630–6.PubMedGoogle Scholar
  22. 22.
    Sanchez MC, Benitez A, Ortloff L, Green LM. Alterations in glutamate uptake in NT2-derived neurons and astrocytes after exposure to gamma radiation. Radiat Res. 2009;171(1):41–52.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol. 2004;188(2):316–30.PubMedGoogle Scholar
  24. 24.
    Rogers LR. Cerebrovascular complications in cancer patients. Neurol Clin. 2003;21(1):167–92.PubMedGoogle Scholar
  25. 25.
    Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res. 2004;162(1):39–47.PubMedGoogle Scholar
  26. 26.
    Puspitasari A, Koganezawa N, Ishizuka Y, Kojima N, Tanaka N, Nakano T, et al. X irradiation induces acute cognitive decline via transient synaptic dysfunction. Radiat Res. 2016;185(4):423–30.PubMedGoogle Scholar
  27. 27.
    O’Connor MM, Mayberg MR. Effects of radiation on cerebral vasculature: a review. Neurosurgery. 2000;46(1):138–49 discussion 50–1.PubMedGoogle Scholar
  28. 28.
    Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol. 2003;16(2):129–34.PubMedGoogle Scholar
  29. 29.
    Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 2003;63(14):4021–7.PubMedGoogle Scholar
  30. 30.
    Kurita H, Kawahara N, Asai A, Ueki K, Shin M, Kirino T. Radiation-induced apoptosis of oligodendrocytes in the adult rat brain. Neurol Res. 2001;23(8):869–74.PubMedGoogle Scholar
  31. 31.
    Ji S, Tian Y, Sun R, Lu Y, Zhang L, Chen L, et al. Radiation-induced hippocampal neurogenesis impairment and cognitive deficits is associated with inhibition of BDNF-Trk-B signaling. Int J Radiat Oncol Biol Phys. 87(2):S628.Google Scholar
  32. 32.
    Irvine KA, Blakemore WF. A different regional response by mouse oligodendrocyte progenitor cells (OPCs) to high-dose X-irradiation has consequences for repopulating OPC-depleted normal tissue. Eur J Neurosci. 2007;25(2):417–24.PubMedGoogle Scholar
  33. 33.
    Hsu YC, Wang LF, Lee KW, Ho KY, Huang CJ, Kuo WR. Cerebral radionecrosis in patients with nasopharyngeal carcinoma. Kaohsiung J Med Sci. 2005;21(10):452–9.PubMedGoogle Scholar
  34. 34.
    Chari DM, Huang WL, Blakemore WF. Dysfunctional oligodendrocyte progenitor cell (OPC) populations may inhibit repopulation of OPC depleted tissue. J Neurosci Res. 2003;73(6):787–93.PubMedGoogle Scholar
  35. 35.
    Chakraborti A, Allen A, Allen B, Rosi S, Fike JR. Cranial irradiation alters dendritic spine density and morphology in the hippocampus. PLoS One. 2012;7(7):e40844.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Brown WR, Thore CR, Moody DM, Robbins ME, Wheeler KT. Vascular damage after fractionated whole-brain irradiation in rats. Radiat Res. 2005;164(5):662–8.PubMedGoogle Scholar
  37. 37.
    Brown WR, Blair RM, Moody DM, Thore CR, Ahmed S, Robbins ME, et al. Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia. J Neurol Sci. 2007;257(1–2):67–71.PubMedGoogle Scholar
  38. 38.
    Atkinson SL, Li YQ, Wong CS. Apoptosis and proliferation of oligodendrocyte progenitor cells in the irradiated rodent spinal cord. Int J Radiat Oncol Biol Phys. 2005;62(2):535–44.PubMedGoogle Scholar
  39. 39.
    Kyrkanides S, Moore AH, Olschowka JA, Daeschner JC, Williams JP, Hansen JT, et al. Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury. Brain Res Mol Brain Res. 2002;104(2):159–69.PubMedGoogle Scholar
  40. 40.
    Zhou K, Bostrom M, Ek CJ, Li T, Xie C, Xu Y, et al. Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum. Sci Rep. 2017;7:46181.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Zhang J, Tong F, Cai Q, Chen LJ, Dong JH, Wu G, et al. Shenqi fuzheng injection attenuates irradiation-induced brain injury in mice via inhibition of the NF-kappaB signaling pathway and microglial activation. Acta Pharmacol Sin. 2015;36(11):1288–99.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Yoritsune E, Furuse M, Kuwabara H, Miyata T, Nonoguchi N, Kawabata S, et al. Inflammation as well as angiogenesis may participate in the pathophysiology of brain radiation necrosis. J Radiat Res. 2014;55(4):803–11.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Xu P, Xu Y, Hu B, Wang J, Pan R, Murugan M, et al. Extracellular ATP enhances radiation-induced brain injury through microglial activation and paracrine signaling via P2X7 receptor. Brain Behav Immun. 2015;50:87–100.PubMedGoogle Scholar
  44. 44.
    Schnegg CI, Kooshki M, Hsu FC, Sui G, Robbins ME. PPARdelta prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-kappaB and inhibition of the PKCalpha/MEK1/2/ERK1/2/AP-1 pathway. Free Radic Biol Med. 2012;52(9):1734–43.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Schindler MK, Forbes ME, Robbins ME, Riddle DR. Aging-dependent changes in the radiation response of the adult rat brain. Int J Radiat Oncol Biol Phys. 2008;70(3):826–34.PubMedGoogle Scholar
  46. 46.
    Ramanan S, Kooshki M, Zhao W, Hsu F-C, Robbins ME. PPARα ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways. Free Radic Biol Med. 2008;45(12):1695–704.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Hwang SY, Jung JS, Kim TH, Lim SJ, Oh ES, Kim JY, et al. Ionizing radiation induces astrocyte gliosis through microglia activation. Neurobiol Dis. 2006;21(3):457–67.PubMedGoogle Scholar
  48. 48.
    Acharya MM, Green KN, Allen BD, Najafi AR, Syage A, Minasyan H, et al. Elimination of microglia improves cognitive function following cranial irradiation. Sci Rep. 2016;6:31545.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Robbins ME, Zhao W, Garcia-Espinosa MA, Diz DI. Renin-angiotensin system blockers and modulation of radiation-induced brain injury. Curr Drug Targets. 2010;11(11):1413–22.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Robbins ME, Payne V, Tommasi E, Diz DI, Hsu FC, Brown WR, et al. The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys. 2009;73(2):499–505.PubMedGoogle Scholar
  51. 51.
    Robbins ME, Zhao W. Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol. 2004;80(4):251–9.PubMedGoogle Scholar
  52. 52.
    • Peiffer AM, Leyrer CM, Greene-Schloesser DM, Shing E, Kearns WT, Hinson WH, et al. Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline. Neurology. 2013;80(8):747–53 This was an important analysis of several prospective studies which linked post-RT cognitive function to the dose distribution in the brain relative to specific anatomic regions-of-interest. This suggests that ultimatley, a dose-volume-histogram analysis of neural substructures could help predict (and reduce the risk) of RICD.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Yoshita M, Fletcher E, Harvey D, Ortega M, Martinez O, Mungas DM, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology. 2006;67(12):2192–8.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Kester MI, Goos JD, Teunissen CE, Benedictus MR, Bouwman FH, Wattjes MP, et al. Associations between cerebral small-vessel disease and Alzheimer disease pathology as measured by cerebrospinal fluid biomarkers. JAMA Neurol. 2014;71(7):855–62.PubMedGoogle Scholar
  55. 55.
    Capizzano A, Acion L, Bekinschtein T, Furman M, Gomila H, Martinez A, et al. White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004;75(6):822–7.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Brickman AM, Muraskin J, Zimmerman ME. Structural neuroimaging in Alzheimer’s disease: do white matter hyperintensities matter? Dialogues Clin Neurosci. 2009;11(2):181–90.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Brickman AM, Honig LS, Scarmeas N, Tatarina O, Sanders L, Albert MS, et al. Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease. Arch Neurol. 2008;65(9):1202–8.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Brickman AM. Contemplating Alzheimer’s disease and the contribution of white matter hyperintensities. Curr Neurol Neurosci Rep. 2013;13(12):415.  https://doi.org/10.1007/s11910-013-0415-7.CrossRefPubMedGoogle Scholar
  59. 59.
    Johannesen TB, Lien HH, Hole KH, Lote K. Radiological and clinical assessment of long-term brain tumour survivors after radiotherapy. Radiother Oncol. 2003;69(2):169–76.PubMedGoogle Scholar
  60. 60.
    Constine LS, Konski A, Ekholm S, McDonald S, Rubin P. Adverse effects of brain irradiation correlated with MR and CT imaging. Int J Radiat Oncol Biol Phys. 1988;15(2):319–30.PubMedGoogle Scholar
  61. 61.
    Tsuruda JS, Kortman KE, Bradley WG, Wheeler DC, Van Dalsem W, Bradley TP. Radiation effects on cerebral white matter: MR evaluation. AJR Am J Roentgenol. 1987;149(1):165–71.PubMedGoogle Scholar
  62. 62.
    Chapman CH, Nagesh V, Sundgren PC, Buchtel H, Chenevert TL, Junck L, et al. Diffusion tensor imaging of normal-appearing white matter as biomarker for radiation-induced late delayed cognitive decline. Int J Radiat Oncol Biol Phys. 2012;82(5):2033–40.PubMedGoogle Scholar
  63. 63.
    Chapman CH, Zhu T, Nazem-Zadeh M, Tao Y, Buchtel HA, Tsien CI, et al. Diffusion tensor imaging predicts cognitive function change following partial brain radiotherapy for low-grade and benign tumors. Radiother Oncol. 2016;120(2):234–40.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Mabbott DJ, Noseworthy MD, Bouffet E, Rockel C, Laughlin S. Diffusion tensor imaging of white matter after cranial radiation in children for medulloblastoma: correlation with IQ. Neuro-Oncology. 2006;8(3):244–52.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Laukkanen E, Klonoff H, Allan B, Graeb D, Murray N. The role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae. Int J Radiat Oncol Biol Phys. 1988;14(6):1109–17.PubMedGoogle Scholar
  66. 66.
    Meyers CA, Wefel JS. The use of the mini-mental state examination to assess cognitive functioning in cancer trials: no ifs, ands, buts, or sensitivity. J Clin Oncol. 2003;21(19):3557–8.PubMedGoogle Scholar
  67. 67.
    Noll KR, Bradshaw ME, Rexer J, Wefel JS. Neuropsychological practice in the oncology setting. Arch Clin Neuropsychol. 2018;33(3):344–53.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Meyers CA, Hess KR. Multifaceted end points in brain tumor clinical trials: cognitive deterioration precedes MRI progression. Neuro-Oncology. 2003;5(2):89–95.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Ferguson RJ, Ahles TA, Saykin AJ, McDonald BC, Furstenberg CT, Cole BF, et al. Cognitive-behavioral management of chemotherapy-related cognitive change. Psychooncology. 2007;16(8):772–7.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Tombaugh TN. Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol. 2004;19(2):203–14.PubMedGoogle Scholar
  71. 71.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303–8.PubMedGoogle Scholar
  72. 72.
    Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270–9.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004;256(3):240–6.PubMedGoogle Scholar
  74. 74.
    Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535–62.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256(3):183–94.Google Scholar
  76. 76.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–9.PubMedPubMedCentralGoogle Scholar
  77. 77.
    McKhann G, Drachman D, Folstein MF, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939–44.PubMedGoogle Scholar
  78. 78.
    American Psychiatric Association. American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994. xxvii, 886 p. p.Google Scholar
  79. 79.
    Gifford A, Lawrence J, Case D, Rapp S, Baker L, Craft S, et al. Mild cognitive impairment (MCI) in chemotherapy-treated breast cancer survivors. J Clin Oncol. 2015;33(15):9560.Google Scholar
  80. 80.
    Gifford AR, Lawrence JA, Baker LD, Balcueva EP, Case D, Craft S, 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).Google Scholar
  81. 81.
    Cramer CK, McKee N, Case LD, Chan MD, Cummings TL, Lesser GJ, et al. Mild cognitive impairment in long-term brain tumor survivors following brain irradiation. J Neurooncol. 2018.Google Scholar
  82. 82.
    Naughton MJ, Case LD, Peiffer A, Chan M, Stieber V, Moore D, et al. Quality of life of irradiated brain tumor survivors treated with donepezil or placebo: results of the WFU CCOP research base protocol 91105. Neurooncol Pract. 2018;5(2):114–21.PubMedGoogle Scholar
  83. 83.
    Mulhern RK, Khan RB, Kaplan S, Helton S, Christensen R, Bonner M, et al. Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer. J Clin Oncol. 2004;22(23):4795–803.PubMedGoogle Scholar
  84. 84.
    Bruera E, Driver L, Barnes EA, Willey J, Shen L, Palmer JL, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol. 2003;21(23):4439–43.PubMedGoogle Scholar
  85. 85.
    Page BR, Shaw EG, Lu L, Bryant D, Grisell D, Lesser GJ, et al. Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue. Neuro-Oncology. 2015;17(10):1393–401.PubMedPubMedCentralGoogle Scholar
  86. 86.
    van der Linden SD, Sitskoorn MM, Rutten GM, Gehring K. Feasibility of the evidence-based cognitive telerehabilitation program Remind for patients with primary brain tumors. J Neuro-Oncol. 2018;137(3):523–32.Google Scholar
  87. 87.
    •• Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037–44 This randomized trial of SRS alone versus SRS + WBRT for patients with a limited number of brain metastases demonstrated that treating patients with SRS rather than WBRT can preserve their cognition without compromising overall survival. At 4 months, only 24% of patients receiving SRS had declined in their HVLT-R score compared to 52% of patients in the WBRT arm.PubMedGoogle Scholar
  88. 88.
    •• Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316(4):401–9 N0574 randomized patients with 1–3 brain metastases to SRS alone or SRS + WBRT and showed a much higher incidence of cognitive decline in the group receiving WBRT than those receiving SRS alone.PubMedPubMedCentralGoogle Scholar
  89. 89.
    •• Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC.3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1049–60 NCGTGN107C/CEC 3 offered confirmation that cognitive-deterioration-free survival is longer in patients receiving SRS compared to WBRT. In this phase III trial, 194 patients who had undergone resection for a brain metastasis < 5 cm were randomized to postoperative SRS to the surgical cavity or WBRT [90]. At 6 months, 52% of patients receiving SRS had cognitive decline compared with 85% of the patients receiving WBRT. Again, there was no difference seen in survival between the two groups. This was a landmark trial and will likely serve as a benchmark and historical control study for some years to come.PubMedPubMedCentralGoogle Scholar
  90. 90.
    •• Gondi V, Deshmukh S, Brown PD, Wefel JS, Tome WA, Bruner DW, et al. Preservation of neurocognitive function (NCF) with conformal avoidance of the hippocampus during whole-brain radiotherapy (HA-WBRT) for brain metastases: preliminary results of phase III trial NRG Oncology CC001. Int J Radiat Oncol Biol Phys. 2018;102(5):1607 This is an initial report of a trial looking at WBRT plus memantine versus WBRT with hippocampal avoidance plus memantine (CC001). The early results indicate that time to cognitive decline is longer in the hippocampal avoidance + memantine versus WBRT + memantine.Google Scholar
  91. 91.
    Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson’s disease. J Neurochem. 2002;82(3):615–24.Google Scholar
  92. 92.
    Chang KL, Pee HN, Yang S, Ho PC. Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer’s disease. Sci Rep. 2015;5:9000.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB. Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem. 2004;88(2):494–501.Google Scholar
  94. 94.
    Sundararajan S, Gamboa JL, Victor NA, Wanderi EW, Lust WD, Landreth GE. Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia. Neuroscience. 2005;130(3):685–96.PubMedGoogle Scholar
  95. 95.
    Zhao Y, Patzer A, Gohlke P, Herdegen T, Culman J. The intracerebral application of the PPARgamma-ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain. Eur J Neurosci. 2005;22(1):278–82.PubMedGoogle Scholar
  96. 96.
    Cramer CK, Alphonse-Sullivan N, Isom S, Metheny-Barlow LJ, Cummings TL, Page BR, et al. Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial. J Cancer Res Clin Oncol. 2018.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Christina K. Cramer
    • 1
    Email author
  • Tiffany L. Cummings
    • 2
  • Rachel N. Andrews
    • 3
  • Roy Strowd
    • 4
  • Stephen R. Rapp
    • 5
  • Edward G. Shaw
    • 6
  • Michael D. Chan
    • 1
  • Glenn J. Lesser
    • 7
  1. 1.Department of Radiation OncologyWake Forest Baptist Medical CenterWinston-SalemUSA
  2. 2.Department of NeurologyWake Forest Baptist Medical CenterWinston-SalemUSA
  3. 3.Department of Radiation Oncology, Section on Radiation BiologyWake Forest Baptist Medical CenterWinston-SalemUSA
  4. 4.Department of Hematology/OncologyWake Forest Baptist Medical CenterWinston-SalemUSA
  5. 5.Department of Psychiatry and Behavioral Medicine and Division Public Health Sciences (Social Sciences and Health Policy)Wake Forest School of MedicineWinston-SalemUSA
  6. 6.Memory Counseling Program, Section on Gerontology and Geriatric Medicine, Sticht Center on Healthy Aging and Alzheimer’s PreventionWake Forest Baptist HealthWinston-SalemUSA
  7. 7.Oncology, Medical Neuro-Oncology and Neuro-Oncology Research ProgramWake Forest Baptist Comprehensive Cancer CenterWinston-SalemUSA

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