Radiation-induced brain injury: A review

Dana Greene-Schloesser, Mike E Robbins, Ann M Peiffer, Edward G Shaw, Kenneth T Wheeler, Michael D Chan, Dana Greene-Schloesser, Mike E Robbins, Ann M Peiffer, Edward G Shaw, Kenneth T Wheeler, Michael D Chan

Abstract

Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their integration at clinically relevant doses and schedules. Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

Keywords: brain injury; hippocampal changes; metastatic brain tumor; pathogenesis; radiation-induced.

Figures

FIGURE 1
FIGURE 1
Symptoms and timeline for the development of radiation-induced brain injury in patients treated with fWBI.
FIGURE 2
FIGURE 2
The percentage of patients developing radiation-induced cognitive impairment as a function of time after fWBI. Adapted from Nieder et al. (1999).
FIGURE 3
FIGURE 3
Development of radiation-induced cognitive impairment as a function of time after young adult male Fischer 344 X Brown Norway rats were irradiated with a total 40 Gy dose of fWBI delivered as 5 Gy fractions, twice/week for 4 weeks. Cognition was assessed using the novel object recognition (NOR) task. The sham-irradiated group value is the average of the NOR scores from unirradiated rats at all of the time points. In this rat model, cognitive impairment is both progressive and not significantly different from sham-irradiated rats until ~6 months after fWBI, similar to what is observed in the clinic. ***P <0.001.
FIGURE 4
FIGURE 4
Diffusion tensor image of a rat brain color-coded to show the predominant direction of diffusion in various brain regions; blue indicates diffusion between anterior (A) and posterior (P), red indicates flow between left (L) and right (R), and green indicates flow between superior (S) and inferior (I). Adapted from Robbins et al. (2012).
FIGURE 5
FIGURE 5
[18F]FDG-PET scans of cerebral glucose metabolism 9 months after fWBI of young adult male non-human primates.Upper panel: post-fWBI < Pre-fWBI. Blue areas in the cuneate cortex and prefrontal cortex exhibited less metabolic activity in scans obtained 9 months after fWBI than in scans obtained prior to fWBI. Lower panel: post-fWBI > Pre-fWBI: the red areas in the cerebellum and thalamus exhibited greater metabolic activity in scans obtained 9 months after fWBI than in scans obtained prior to fWBI. The color bar is the degree of intensity difference shown as a scale of t values with P <0.001. Adapted from Robbins et al. (2012).
FIGURE 6
FIGURE 6
Both RAS inhibitors and PPAR agonists prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months post-irradiation using the NOR task. Rats were administered, (A) the ARB, L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, fenofibrate, before, during, and for 29 weeks post-fWBI; tested at 26 weeks. *P <0.05, **P <0.01, ***P <0.001 compared to sham-irradiated rats.

References

    1. Acharya M. M., Christie L. A., Lan M. L., Donovan P. J., Cotman C. W., Fike J. R., Limoli C. L. (2009). Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. 106 19150–19155
    1. Acharya M. M., Christie L. A., Lan M. L., Giedzinski E., Fike J. R., Rosi S., Limoli C. L. (2011). Human neural stem cell transplantation ameliorates radiation-induced cognitive dysfunction. Cancer Res. 71 4834–4845
    1. Armstrong C., Ruffer J., Corn B., DeVries K., Mollman J. (1995). Biphasic patterns of memory deficits following moderate-dose partial-brain irradiation: neuropsychologic outcome and proposed mechanisms. J. Clin. Oncol. 13 2263–2271
    1. Atwood T., Payne V. S., Zhao W., Brown W. R., Wheeler K. T., Zhu J. M., Robbins M. E. (2007). Quantitative magnetic resonance spectroscopy reveals a potential relationship between radiation-induced changes in rat brain metabolites and cognitive impairment. Radiat. Res. 168 574–581
    1. Barani I. J., Benedict S. H., Lin P. S. (2007a). Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies. Int. J. Radiat. Oncol. Biol. Phys. 68 324–333
    1. Barani I. J., Cuttino L. W., Benedict S. H., Todor D., Bump E. A., Wu Y., Chung T. D., Broaddus W. C., Lin P. S. (2007b). Neural stem cell-preserving external-beam radiotherapy of central nervous system malignancies. Int. J. Radiat. Oncol. Biol. Phys. 68 978–985
    1. Bassant M. H., Court L. (1978). Effects of whole-body irradiation on the activity of rabbit hippocampal neurons. Radiat. Res. 75 593–606
    1. Bellinzona M., Gobbel G. T., Shinohara C., Fike J. R. (1996). Apoptosis is induced in the subependyma of young adult rats by ionizing irradiation. Neurosci. Lett. 208 163–166
    1. Blumberg B., Evans R. M. (1998). Orphan nuclear receptors – new ligands and new possibilities. Genes Dev. 12 3149–3155
    1. Bright J. J., Kanakasabai S., Chearwae W., Chakraborty S. (2008). PPAR regulation of inflammatory signaling in CNS diseases. PPAR Res. 2008 658520
    1. Brown W. R., Blair R. M., Moody D. M., Thore C. R., Ahmed S., Robbins M. E., Wheeler K. T. (2007). Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia. J. Neurol. Sci. 257 67–71
    1. Brown W. R., Thore C. R., Moody D. M., Robbins M. E., Wheeler K. T. (2005). Vascular damage after fractionated whole-brain irradiation in rats. Radiat. Res. 164 662–668
    1. Calvo W., Hopewell J. W., Reinhold H. S., Yeung T. K. (1988). Time-and dose-related changes in the white matter of the rat brain after single doses of X rays. Br. J. Radiol.q 61 1043–1052
    1. Chan K. C., Khong P. L., Cheung M. M., Wang S., Cai K. X., Wu E. X. (2009). MRI of late microstructural and metabolic alterations in radiation-induced brain injuries. J. Magn. Reson. Imaging 29 1013–1020
    1. Chan Y. L., Roebuck D. J., Yuen M. P., Yeung K. W., Lau K. Y., Li C. K., Chik K. W. (2001). Long-term cerebral metabolite changes on proton magnetic resonance spectroscopy in patients cured of acute lymphoblastic leukemia with previous intrathecal methotrexate and cranial irradiation prophylaxis. Int. J. Radiat. Oncol. Biol. Phys. 50 759–763
    1. Chang E. L., Wefel J. S., Hess K. R., Allen P. K., Lang F. F., Kornguth D. G., Arbuckle R. B., Swint J. M., Shiu A. S., Maor M. H., Meyers C. A. (2009). Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 10 1037–1044
    1. Chapman C. H., Nagesh V., Sundgren P. C., Buchtel H., Chenevert T. L., Junck L., Lawrence T. S., Tsien C. I., Cao Y. (2012). Diffusion tensor imaging of normal-appearing white matter as biomarker for radiation-induced late delayed cognitive decline. Int. J. Radiat. Oncol. Biol. Phys. 82 2033–2040
    1. Cheung M. M., Chan A. S., Law S. C., Chan J. H., Tse V. K. (2000). Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis. Arch. Neurol. 57 1347–1352
    1. Chiang C. S., Hong J.-H., Stalder A., Sun J.-R., Withers H. R., McBride W. H. (1997). Delayed molecular responses to brain irradiation. Int. J. Radiat. Biol. 72 45–53
    1. Chiang C. S., McBride W. H., Withers H. R. (1993). Radiation-induced astrocytic and microglial responses in mouse brain. Radiother. Oncol. 29 60–68
    1. Chong V. F., Khoo J. B., Chan L. L., Rumpel H. (2002). Neurological changes following radiation therapy for head and neck tumours. Eur. J. Radiol. 44 120–129
    1. Cochran D. C., Chan M. D., Aklilu M., Lovato J. F., Alphonse N. K., Bourland J. D., Urbanic J. J., McMullen K. P., Shaw E. G., Tatter S. B., Ellis T. L. (2012). The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with Gamma Knife surgery. J. Neurosurg. 116 978–983
    1. Conner K. R., Payne V. S., Forbes M. E., Robbins M. E., Riddle D. R. (2010). Effects of the AT1 receptor antagonist L-158,809 on microglia and neurogenesis after fractionated whole-brain irradiation. Radiat. Res. 173 49–61
    1. Crossen J. R., Garwood D., Glatstein E., Neuwelt E. A. (1994). Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J. Clin. Oncol. 12 627–642
    1. Davisson R. L. (2003). Physiological genomic analysis of the brain renin-angiotensin system. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285 R498–R511
    1. DeAngelis L. M., Delattre J. Y., Posner J. B. (1989). Radiation-induced dementia in patients cured of brain metastases. Neurology 39 789
    1. Dellani P. R., Eder S., Gawehn J., Vucurevic G., Fellgiebel A., Müller M. J., Schmidberger H., Stoeter P., Gutjahr P. (2008). Late structural alterations of cerebral white matter in long-term survivors of childhood leukemia. J. Magn. Reson. Imaging 27 1250–1255
    1. DeLong R., Friedman H., Friedman N., Gustafson K., Oakes J. (1992). Methylphenidate in neuropsychological sequelae of radiotherapy and chemotherapy of childhood brain tumors and leukemia. J. Child Neurol. 7 462–463
    1. den Heijer T., Sijens P. E., Prins N. D., Hofman A., Koudstaal P. J., Oudkerk M., Breteler M. M. (2006). MR spectroscopy of brain white matter in the prediction of dementia. Neurology 66 540–544
    1. Derosa G. (2010). Efficacy and tolerability of pioglitazone in patients with type 2 diabetes mellitus: comparison with other oral antihyperglycaemic agents. Drugs 70 1945–1961
    1. Detre J. A., Wang J., Wang Z., Rao H. (2009). Arterial spin-labeled perfusion MRI in basic and clinical neuroscience. Curr. Opin. Neurol. 22 348–355
    1. Dropcho E. J. (1991). Central nervous system injury by therapeutic irradiation. Neurol. Clin. 9 969–988
    1. Eichenbaum H. (2001). The hippocampus and declarative memory: cognitive mechanisms and neural codes. Behav. Brain Res. 127 199–207
    1. Eichenbaum H. (2004). Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44 109–1020
    1. Elkabes S., DiCicco-Bloom E. M., Black I. B. (1996). Brain microglia/macrophages express neurotropins that selectively regulate microglial proliferation and function. J. Neurosci. 16 2508–2521
    1. Esteve F., Rubin C., Grand S., Kolodie H, Le Bas J. F. (1998). Transient metabolic changes observed with proton MR spectroscopy in normal human brain after radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 40 279–286
    1. Frost M. H., Sloan J. A. (2002). Quality of life measurements: a soft outcome-or is it? Am.J. Manag. Care 8 S574–S579
    1. Fukuda H., Fukuda A., Zhu C., Korhonen L., Swanpalmer J., Hertzman S., Leist M., Lannering B., Lindholm D., Björk-Eriksson T., Marky I., Blomgren K. (2004). Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition. Cell Death Differ. 11 1166–1178
    1. Gage F. H., Kempermann G., Palmer T. D., Peterson D. A., Ray J. (1998). Multipotent progenitor cells in the adult dentate gyrus. J. Neurobiol. 36 249–266
    1. Gangloff H., Haley T. J. (1960). Effects of X-irradiation on spontaneous and evoked brain electrical activity in cats. Radiat. Res. 12 694–704
    1. Gard P. R. (2002). The role of angiotensin II in cognition and behaviour. Eur. J. Pharmacol. 438 1–14
    1. Gebicke-Haerter P. J. (2001). Microglia in neurodegeneration: molecular aspects. Microsc. Res. Tech. 54 47–58
    1. Gillies R. J., Morse D. L. (2005). In vivo magnetic resonance spectroscopy in cancer. Annu. Rev. Biomed. Eng. 7 287–326
    1. Giovagnoli A. R., Boiardi A. (1994). Cognitive impairment and quality of life in long-term survivors of malignant brain tumors. Ital. J. Neurol. Sci. 15 481–488
    1. Gleason JF, Jr, Case D, Rapp SR et al. (2007) symptom clusters in newly diagnosed brain tumor patients. J. Support. Oncol. 436 427–433
    1. Gondi V., Hermann B. P., Mehta M. P., Tome W. A. (2011). Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for Benign or low-grade adult brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 83 e487–e493
    1. Grosshans D. R., Meyers C. A., Allen P. K., Davenport S. D., Komaki R. (2008). Neurocognitive function in patients with small cell lung cancer: effect of prophylactic cranial irradiation. Cancer 112 589–595
    1. Gutiérrez A. N., Westerly D. C., Tomé W. A., Jaradat H. A., Mackie T. R., Bentzen S. M., Khuntia D., Mehta M. P. (2007). Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: a planning study. Int. J. Radiat. Oncol. Biol. Phys. 69 589–597
    1. Hansson E. (1988). Astroglia from defined brain regions as studied with primary cultures. Prog. Neurobiol. 30 369–397
    1. Haris M., Kumar S., Raj M. K., Das K. J., Sapru S., Behari S., Rathore R. K., Narayana P. A., Gupta R. K. (2008). Serial diffusion tensor imaging to characterize radiation-induced changes in normal-appearing white matter following radiotherapy in patients with adult low-grade gliomas. Radiat. Med. 26 140–150
    1. Herman M. A., Tremont-Lukats I., Meyers C. A., Trask D. D., Froseth C., Renschler M. F., Mehta M. P. (2003). Neurocognitive and functional assessment of patients with brain metastases: a pilot study. Am. J. Clin. Oncol. 26 273–279
    1. Herynek V., Burian M., Jirák D., Liscák R., Námestková K., Hájek M, Syková E. (2004). Metabolite and diffusion changes in the rat brain after Leksell Gamma Knife irradiation. Magn. Reson. Med. 52 397–402
    1. Hochberg F. H., Slotnick B. (1980). Neuropsychologic impairment in astxocytoma survivors. Neurology 30 172
    1. Hoehn M., Nicolay K., Franke C, van der Sanden B. (2001). Application of magnetic resonance to animal models of cerebral ischemia. J. Magn. Reson. Imaging 14 491–509
    1. Hong J. H., Chiang C. S., Campbell I. L., Sun J. R., Withers H. R., McBride W. H. (1995). Induction of acute phase gene expression by brain irradiation. Int. J. Radiat. Oncol. Biol. Phys. 33 619–626
    1. Hornsey S., Myers R., Coultas P. G., Rogers M. A., White A. (1981). Turnover of proliferative cells in the spinal cord after irradiation and its relation to time dependent repair of radiation damage. Br. J. Radiol. 54 1081–1085
    1. Hsiao K. Y., Yeh S. A., Chang C. C., Tsai P. C., Wu J. M., Gau J. S. (2010). Cognitive function before and after intensity-modulated radiation therapy in patients with nasopharyngeal carcinoma: a prospective study. Int. J. Radiat. Oncol. Biol. Phys. 77 722–726
    1. Hwang S. Y., Jung J. S., Kim T. H., Lim S. J., Oh E. S., Kim J. Y., Ji K. A., Joe E. H., Cho K. H., Han I. O. (2006). Ionizing radiation induces astrocyte gliosis through microglia activation. Neurobiol. Dis. 21 457–467
    1. Janzer R. C., Raff M. C. (1987). Astrocytes induce blood–brain barrier properties in endothelial cells. Nature 325 253–257
    1. Jenrow K. A., Brown S. L., Liu J., Kolozsvary A., Lapanowski K., Kim J. H. (2010). Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus. Radiat. Oncol. 5 6
    1. Johannesen T. B., Lien H. H., Hole K. H., Lote K. (2003). Radiological and clinical assessment of long-term brain tumour survivors after radiotherapy. Radiother. Oncol. 69 169–176
    1. Johansen-Berg H., Behrens T. E. (2006). Just pretty pictures? What diffusion tractography can add in clinical neuroscience. Curr. Opin. Neurol. 19 379–385
    1. Johnson B. E., Patronas N., Hayes W., Grayson J., Becker B., Gnepp D., Rowland J., Anderson A., Glatstein E., Ihde D. C. (1990). Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J. Clin. Oncol. 8 48–56
    1. Joo K. M., Jin J., Kang B. G., Lee S. J., Kim K. H., Yang H., Lee Y. A., Cho Y. J., Im Y. S., Lee D. S., Lim D. H., Kim D. H., Um H. D., Lee S. H., Lee J. I., Nam D. H. (2012). Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage. PLoS ONE 7 e25936 10.1371/ journal.pone.0025936
    1. Kaiser L. G., Schuff N., Cashdollar N., Weiner M. W. (2005). Scyllo-inositol in normal aging human brain: 1 H magnetic resonance spectroscopy study at 4 Tesla. NMR Biomed. 18 51–55
    1. Kalm M., Fukuda A., Fukuda H., Ohrfelt A., Lannering B., Björk-Eriksson T., Blennow K., Márky I., Blomgren K. (2009). Transient inflammation in neurogenic regions after irradiation of the developing brain. Radiat. Res. 171 66–76
    1. Khong P.L., Leung L.H.T., Fung A. S. M., Fong D. Y. T., Qiu D., Kwong D. L., Ooi G. C., McAlonan G., Cao G., Chan G. C. (2006). White matter anisotropy in post-treatment childhood cancer survivors: preliminary evidence of association with neurocognitive function. J. Clin. Oncol. 24 884–890
    1. Kim J. H., Brown S. L., Kolozsvary A., Jenrow K. A., Ryu S., Rosenblum M. L., Carretero O. A. (2004). Modification of radiation injury by ramipril, inhibitor of angiotensin-converting enzyme, on optic neuropathy in the rat. Radiat. Res. 161 137–142
    1. Kim S. U, de Vellis J. (2005). Microglia in health and disease. J. Neurosci. Res. 81 302–313
    1. Klein M., Heimans J. J., Aaronson N. K., van der Ploeg H. M., Grit J., Muller M., Postma T. J., Mooij J. J., Boerman R. H., Beute G. N., Ossenkoppele G. J., van Imhoff G. W., Dekker A. W., Jolles J., Slotman B. J., Struikmans H., Taphoorn M. J. (2002). Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study. Lancet 360 1361–1368
    1. Kondziolka D., Niranjan A., Flickinger J. C., Lunsford L. D. (2005). Radiosurgery with or without whole-brain radiotherapy for brain metastases: the patients’ perspective regarding complications. Am. J. Clin. Oncol. 28 173–179
    1. Kurita H., Kawahara N., Asai A., Ueki K., Shin M., Kirino T. (2001). Radiation-induced apoptosis of oligodendrocytes in the adult rat brain. Neurol. Res. 23 869–874
    1. Kyrkanides S., Moore A. H., Olschowka J. A., Daeschner J. C., Williams J. P., Hansen J. T, Kerry O’Banion M. (2002). Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation-injury. Brain Res. Mol. Brain Res. 104 159–169
    1. Kyrkanides S., Olschowka J. A., Williams J. P., Hansen J. T, O’Banion M. K. (1999). TNF alpha and IL-1beta mediate intercellular adhesion molecule-1 induction via microglia-astrcoyte interaction in CNS radiation injury. J. Neuroimmunol. 95 95–106
    1. Lamproglou I., Chen Q. M., Boisserie G., Mazeron J. J., Poisson M., Baillet F., Le Poncin M., Delattre J. Y. (1995). Radiation-induced cognitive dysfunction: an experimental model in the old rat. Int. J. Radiat. Oncol. Biol. Phys. 31 65–70
    1. Laukkanen E., Klonoff H., Allan B., Graeb D., Murray N. (1988). The role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae. Int. J. Radiat. Oncol. Biol. Phys. 14 1109–1117
    1. Le Bihan D., Mangin J. F., Poupon C., Clark C. A., Pappata S., Molko N., Chabriat H. (2001). Diffusion tensor imaging: concepts and applications. J. Magn. Reson. Imaging 13 534–546
    1. Lee M. C., Pirzkall A., McKnight T. R., Nelson S. J. (2004). 1 H-MRSI of radiation effects in normal-appearing white matter: dose-dependence and impact on automated spectral classification. J. Magn. Reson. Imaging 19 379–388
    1. Lee T. C., Greene-Schloesser D., Payne V., Diz D. I., Hsu F. C., Kooshki M., Mustafa R., Riddle D. R., Zhao W., Chan M. D., Robbins M. E. (2012). Chronic administration of the ACE inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex dependent cognitive impairment. Radiat Res. [Epub ahead of print]
    1. Lee W. H., Cho H. J., Sonntag W. E., Lee Y. W. (2011). Radiation attenuates physiological angiogenesis by differential expression of VEGF, Ang-1, tie-2 and Ang-2 in rat brain. Radiat. Res. 176 753–760
    1. Lee W. H., Sonntag W. E., Mitschelen M., Yan H., Lee Y. W. (2010). Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain. Int. J. Radiat. Biol. 86 132–144
    1. Lee W. H., Warrington J. P., Sonntag W. E., Lee Y. W. (2012). Irradiation alters MMP-2/TIMP-2 system and collagen type iv degradation in brain. Int. J. Radiat. Oncol. Biol. Phys. 82 1559–1566
    1. Leyrer C. M., Peiffer A. M., Greene-Schloesser D. M., Kearns W. T., Hinson W. H., Tatter S. B., Rapp S. R., Robbins M. E., Shaw E. G., Chan M. D. (2011). Normal tissue complication modeling of the brain: dose-volume histogram analysis of neurocognitive outcomes of two CCOP trials. Int. J. Radiat. Oncol. Biol. Phys. 81 S184–S185
    1. Li J., Bentzen S. M., Li J., Renschler M., Mehta M. P. (2008). Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int. J. Radiat. Oncol. Biol. Phys. 71 64–70
    1. Li Y. Q., Chen P., Haimovitz-Friedman A., Reilly R. M., Wong C. S. (2003). Endothelial apoptosis initiates acute blood–brain barrier disruption after ionizing radiation. Cancer Res. 63 5950–5956
    1. Limoli C. L., Rola R., Giedzinski E., Mantha S., Huang T.-T., Fike J. R. (2004). Cell-density-dependent regulation of neural precursor cells function. Proc. Natl. Acad. Sci. U.S.A. 101 16052–16057
    1. Machida M., Lonart G., Britten R. A. (2010). Low (60 cGy) doses of (56)Fe HZE-particle radiation lead to a persistent reduction in the glutamatergic readily releasable pool in rat hippocampal synaptosomes. Radiat. Res. 174 618–623
    1. McKeage K., Keating G. M. (2011). Fenofibrate: a review of its use in dyslipidaemia. Drugs 71 1917–1946
    1. McKinley M. J., Albiston A. L., Allen A. M., Mathai M. L., May C. N., McAllen R. M., Oldfield B. J., Mendelsohn F. A., Chai S. Y. (2003). The brain renin-angiotensin system: location and physiological roles. Int. J. Biochem. Cell Biol. 35 901–918
    1. Meyers C. A., Brown P. D. (2006). Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J. Clin. Oncol. 24 1305–1309
    1. Meyers C. A., Weitzner M. A., Valentine A. D., Levin V. A. (1998). Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. J. Clin. Oncol. 16 2522–2527
    1. Meyers CA, Valentine AD, Levin VA. Methylphenidate to improve neurobehavioral slowing and functional independence in brain tumor patients. Neuro-Oncology 2nd Annual Scientific Meeting, Charlottesville, Virginia, 1997 (abstract 93).
    1. Mildenberger M., Beach T. G., McGeer E. G., Ludgate C. M. (1990). An animal model of prophylactic cranial irradiation: histologic effects at acute, early and delayed stages. Int. J. Radiat. Oncol. Biol. Phys. 18 1051–1060
    1. Mizumatsu S., Monje M. L., Morhardt D. R., Rola R., Palmer T. D., Fike J. R. (2003). Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 63 4021–4027
    1. Molteni A., Moulder J. E., Cohen E. F., Ward W. F., Fish B. L., Taylor J. M., Wolfe L. F., Brizio-Molteni L., Veno P. (2000). Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. Int. J. Radiat. Biol. 76 523–532
    1. Monje M. L., Mizumatsu S., Fike J. R., Palmer T. D. (2002). Irradiation induces neural precursor-cell dysfunction. Nat. Med. 8 955–962
    1. Monje M. L., Toda H., Palmer T. D. (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science 302 1760–1765
    1. Monje M. L., Vogel H., Masek M., Ligon K. L., Fisher P. G., Palmer T. D. (2007). Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann. Neurol. 62 515–520
    1. Moravan M. J., Olschowka J. A., Williams J. P, O’Banion M. K. (2011). Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain. Radiat. Res. 176 459–473
    1. Morris G. M., Coderre J. A., Bywaters A., Whitehouse E., Hopewell J. W. (1996). Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis. Radiat. Res. 146 313–320
    1. Moulder J. E., Fish B. L., Cohen E. P. (2003). ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy. Curr. Pharm. Des. 9 737–749
    1. Nagesh V., Tsien C. I., Chenevert T. L., Ross B. D., Lawrence T. S., Junick L., Cao Y. (2008). Radiation-induced changes in normal-appearing white matter in patients with cerebral tumors: a diffusion tensor imaging study. Int. J. Radiat. Oncol. Biol. Phys. 70 1002–1010
    1. Naylor A. S., Bull C., Nilsson M. K., Zhu C., Björk-Eriksson T., Eriksson P. S., Blomgren K., Kuhn H. G. (2008). From the cover: voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain. Proc. Natl. Acad. Sci. U.S.A. 105 14632–14637
    1. Nieder C., Leicht A., Motaref B., Nestle U., Niewald M., Schnabel K. (1999). Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs. Am. J. Clin. Oncol. 22 573–579
    1. Noel F., Gumin G. J., Raju U., Tofilon P. J. (1998). Increased expression of prohormone convertase-2 in the irradiated rat brain. FASEB J. 12 1725–1730
    1. Palmer T. D., Takahashi J., Gage F. H. (1997). The adult rat hippocampus contains primordial neural stem cells. Mol. Cell. Neurosci. 8 389–404
    1. Palmer T. D., Willhoite A. R., Gage F. H. (2000). Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425 479–494
    1. Pasantes-Morales H., Franco R., Torres-Marquez M. E., Hernandez-Fonseca K., Ortega A. (2000). Amino acid osmolytes in regulatory volume decrease and isovolumetric regulation in brain cells: contribution and mechanisms. Cell. Physiol. Biochem. 10 361–370
    1. Pellmar T. C., Lepinski D. L. (1993). Gamma radiation (5–10 Gy) impairs neuronal functionin the guinea pig hippocampus. Radiat. Res. 136 255–261
    1. Pocock J. M., Liddle A. C. (2001). Microglial signalling cascades in neurodegenerative disease. Prog. Brain Res. 132 555–565
    1. Qiu D., Kwong D. L., Chan G. C., Leung L. H., Khong P. L. (2007). Diffusion tensor magnetic resonance imaging finding of discrepant fractional anisotropy between the frontal and parietal lobes after whole-brain irradiation in childhood medulloblastoma survivors: reflection of regional white matter radiosensitivity? Int.J. Radiat. Oncol. Biol. Phys. 69 846–851
    1. Raber J., Rola R., LeFevour A., Morhardt D., Curley J., Mizumatsu S., VandenBerg S. R., Fike J. R. (2004). Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat. Res. 162 39–47
    1. Raff M. C., Miller R. H., Noble M. (1983). A glial progenitor cell that develops in vitro into an astrcoyte or an oligodendrocyte depending on culture medium. Nature 303 390–396
    1. Raju U., Gumin G. J., Tofilon P. J. (1999). NFκB activity and target gene expression in the rat brain after one or two exposures to ionizing radiation. Radiat. Oncol. Invest. 7 145–152
    1. Ramanan S., Kooshki M., Zhao W., Hsu F. C., Robbins M. E. (2008). PPARalpha ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-kappaB and AP-1 pathways. Free Radic. Biol. Med. 45 1695–1704
    1. Ramanan S., Kooshki M., Zhao W., Hsu F. C., Riddle D. R., Robbins M. E. (2009). The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int. J. Radiat. Oncol. Biol. Phys. 75 870–877
    1. Ramanan S., Zhao W., Riddle D. R., Robbins M. E. (2010). Role of PPARs in radiation-induced brain injury. PPAR Res. 2010 234975
    1. Reinhold H. S., Calvo W., Hopewell J. W, van den Berg A. P. (1990). Development of blood vessel-related radiation damage in the fimbria of the central nervous system. Int. J. Radiat. Oncol. Biol. Phys. 18 37–42
    1. Robbins M. E., Bourland J. D., Cline J. M., Wheeler K. T., Deadwyler S. A. (2011). A model for assessing cognitive impairment after fractionated whole-brain irradiation in nonhuman primates. Radiat. Res. 175 519–525
    1. Robbins M. E., Brunso-Bechtold J. K., Peiffer A. M., Tsien C. I., Bailey J. E., Marks L. B. (2012). Imaging radiation-induced normal tissue injury. Radiat. Res. 177 449–466
    1. Robbins M. E., Payne V., Tommasi E., Diz D. I., Hsu F. C., Brown W. R., Wheeler K. T., Olson J., Zhao W. (2009). The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int. J. Radiat. Oncol. Biol. Phys. 73 499–505
    1. Robbins M. E., Zhao W. (2004). Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int. J. Radiat. Biol. 80 251–259
    1. Rohde B. H., Rea M. A., Simon J. R., McBride W. J. (1979). Effects of X-irradiation induced loss of cerebellar granule cells on the synaptosomal levels and the high affinity uptake of amino acids. J. Neurochem. 32 1431–1435
    1. Rola R., Raber J., Rizk A., Otsuka S., VandenBerg S. R., Morhardt D. R., Fike J. R. (2004). Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp. Neurol. 188 316–330
    1. Rola R., Sarkissian V., Obenaus A., Nelson G. A., Otsuka S., Limoli C. L., Fike J. R. (2005). High-LET radiation induces inflammation and persistent changes in markers of hippocampal neurogenesis. Radiat. Res. 164 556–560
    1. Roman D. D., Sperduto P. W. (1995). Neuropsychological effects of cranial radiation: current knowledge and future directions. Int. J. Radiat. Oncol. Biol. Phys. 31 983–998
    1. Rosenschold P. M., Engelholm S., Ohlhues L., Law I., Vogelius I., Engelholm S. A. (2011). Photon and proton therapy planning comparison for malignant glioma based on CT, FDG-PET, DTI-MRI and fiber tracking. Acta Oncol. 50 777–783
    1. Rosi S., Andres-Mach M., Fishman K. M., Levy W., Ferguson R. A., Fike J. R. (2008). Cranial irradiation alters the behaviorally induced immediate-early gene Arc (activity-regulated cytoskeleton-associated protein). Cancer Res. 68 9763–9770
    1. Ryu S., Kolozsvary A., Jenrow K. A., Brown S. L., Kim J. H. (2007). Mitigation of radiation-induced optic neuropathy in rats by ACE inhibitor ramipril: importance of ramipril dose and treatment time. J. Neurooncol. 82 119–124
    1. Schindler M. K., Forbes M. E., Robbins M. E., Riddle D. R. (2008). Aging-dependent changes in the radiation response of the adult rat brain. Int. J. Radiat. Oncol. Biol. Phys. 70 826–834
    1. Schlemmer H. P., Bachert P., Henze M., Buslei R., Herfarth K. K., Debus J, van Kaick G. (2002). Differentiation of radiation necrosis from tumor progression using proton magnetic resonance spectroscopy. Neuroradiology 44 216–222
    1. Schultheiss T. E., Stephens L. C. (1992). Permanent radiation myelopathy. Br. J. Radiol. 65 737–753
    1. Scott J. N., Rewcastle N. B., Brasher P. M., Fulton D., MacKinnon J. A., Hamilton M., Cairncross J. G., Forsyth P. (1999). Which glioblastoma multiforme patient will become a long-term survivor? A population-based study. Ann. Neurol. 46 183–188
    1. Seifert G., Schilling K., Steinhauser C. (2006). Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat. Rev. Neurosci. 7 194–206
    1. Seth P., Koul N. (2008). Astrocyte, the star avatar: redefined. J. Biosci. 33 405–421
    1. Shaw E. G., Rosdhal R., D’Agostino R. B., Jr., Lovato J., Naughton M. J., Robbins M. E., Rapp S. R. (2006). Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. J. Clin. Oncol. 24 1415–1420
    1. Shaw E, Arusell R, Scheithauer B et al. (2002) A prospective randomized trial of low-versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a NCCTG-RTOG-ECOG Study. J. Clin. Oncol. 20 2267–2276
    1. Shi L., Adams M. M., Long A., Carter C. C., Bennett C., Sonntag W. E., Nicolle M. M., Robbins M., D’Agostino R., Brunso-Bechtold J. K. (2006). Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat. Res. 166 892–899
    1. Shi L., Linville M. C., Iversen E., Molina D. P., Yester J., Wheeler K. T., Robbins M. E., Brunso-Bechtold J. K. (2009). Maintenance of white matter integrity in a rat model of radiation-induced cognitive impairment. J. Neurol. Sci. 285 178–184
    1. Shi L., Molina D. P., Robbins M. E., Wheeler K. T., Brunso-Bechtold J. K. (2008). Hippocampal neuron number is unchanged 1 year after fractionated whole-brain irradiation at middle age. Int. J. Radiat. Oncol. Biol. Phys. 71 526–532
    1. Shi L., Olson J., D’Agostino R., Jr., Linville C., Nicolle M. M., Robbins M. E., Wheeler K. T., Brunso-Bechtold J. K. (2011). Aging masks detection of radiation-induced brain injury. Brain Res. 1385 307–316
    1. Shinohara C., Gobbel G. T., Lamborn K. R., Tada E., Fike J. R. (1997). Apoptosis in the subependyma of young adult rats after single and fractionated doses of X-rays. Cancer Res. 57 2694–2702
    1. Shrieve D. C., Tarbell N. J., Alexander E., III, Kooy H. M., Black P. M., Dunbar S., Loeffler J. S. (1994). Stereotactic radiotherapy: a technique for dose optimization and escalation for intracranial tumors. Acta Neurochir. Suppl. 62 118–123
    1. Snyder J. S., Kee N., Wojtowicz J. M. (2001). Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus. J. Neurophysiol. 85 2423–2431
    1. Song H., Stevens C. F., Gage F. H. (2002). Astroglia induce neurogenesis from adult neural stem cells. Nature 417 39–44
    1. Stahel P. F., Smith W. R., Bruchis J., Rabb C. H. (2008). Peroxisome proliferator-activated receptors: “Key” regulators of neuroinflammation after traumatic brain injury. PPAR Res. 2008 538141
    1. Stoll G., Jander S. (1999). The role of microglia and macrophages in the pathophysiology of the CNS. Prog. Neurobiol. 58 233–247
    1. Stupp R., Mason W. P., van den Bent M. J., Weller M., Fisher B., Taphoorn M. J., Belanger K., Brandes A. A., Marosi C., Bogdahn U., Curschmann J., Janzer R. C., Ludwin S. K., Gorlia T., Allgeier A., Lacombe D., Cairncross J. G., Eisenhauer E., Mirimanoff R. O, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352 987–996
    1. Sundgren P. C., Cao Y. (2009). Brain irradiation: effects on normal brain parenchyma and radiation injury. Neuroimaging Clin. N. Am. 19 657–668
    1. Sundgren P. C., Nagesh V., Elias A., Tsien C., Junck L., Gomez Hassan D. M., Lawrence T. S., Chenevert T. L., Rogers L., McKeever P., Cao Y. (2009). Metabolic alterations: a biomarker for radiation-induced normal brain injury-an MR spectroscopy study. J. Magn. Reson. Imaging 29 291–297
    1. Taphoorn M. J., Schiphorst A. K., Snoek F. J., Lindeboom J., Wolbers J. G., Karim A. B., Huijgens P. C., Heimans J. J. (1994). Cognitive functions and quality of life in patients with low-grade gliomas: the impact of radiotherapy. Ann. Neurol. 36 48–54
    1. Thotala D. K., Hallahan D. E., Yazlovitskaya E. M. (2008). Inhibition of glycogen synthase kinase 3β attenuates neurocognitive dysfunction resulting from cranial irradiation. Cancer Res. 68 5859–5868
    1. Tofilon P. J., Fike J. R. (2000). The radioresponse of the central nervous system: a dynamic process. Radiat. Res. 153 357–370
    1. Tofts P. S., Brix G., Buckley D. L., Evelhoch J. L., Henderson E., Knopp M. V., Larsson H. B., Lee T. Y., Mayr N. A., Parker G. J., Port R. E., Taylor J., Weisskoff R. M. (1999). Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J. Magn. Reson. Imaging 10 223–232
    1. Torres I. J., Mundt A. J., Sweeney P. J., Llanes-Macy S., Dunaway L., Castillo M., Macdonald R. L. (2003). A longitudinal neuropsychological study of partial brain radiation in adults with brain tumors. Neurology 60 1113–1118
    1. Twijnstra A., Boon P. J., Lormans A. C, ten Velde G. P. (1987). Neurotoxicity of prophylactic cranial irradiation in patients with small cell carcinoma of the lung. Eur. J. Cancer Clin. Oncol. 23 983–986
    1. van den Maazen R. W. M., Kleiboer B. J., Berhagen I, van der Kogel A. J. (1993). Repair capacity of adult rat glial progenitor cells determined by an in vitro clonogenic assay after in vitro or in vivo fractionated irradiation. Int. J. Radiat. Biol. 63 661–666
    1. Vigliani M. C., Duyckaerts C., Hauw J. J., Poisson M., Magdelenat H., Delattre J. Y. (1999). Dementia following treatment of brain tumors with radiotherapy administered alone or in combination with nitrosourea-based chemotherapy: a clinical and pathological study. J. Neurooncol. 41 137–149
    1. Virta A., Patronas N., Raman R., Dwyer A., Barnett A., Bonavita S., Tedeschi G., Lundbom N. (2000). Spectroscopic imaging of radiation-induced effects in the white matter of glioma patients. Magn. Reson. Imaging 18 851–857
    1. Vlkolinsky R., Krucker T., Nelson G. A., Obenaus A. (2008). (56)Fe-particle radiation reduces neuronal output and attenuates lipopolysaccharide-induced inhibition of long-term potentiation in the mouse hippocampus. Radiat. Res. 169 523–530
    1. Walecki J., Sokól M., Pieniazek P., Maciejewski B., Tarnawski R., Krupska T., Wydmañski J., Brzeziñski J., Grieb P. (1999). Role of short TE 1 H-MR spectroscopy in monitoring of post-operation irradiated patients. Eur. J. Radiol. 30 154–161
    1. Warrington J. P., Csiszar A., Johnson D. A., Herman T. S., Ahmad S., Lee Y. W., Sonntag W. E. (2011a). Cerebral microvascular rarefaction induced by whole brain radiation is reversible by systemic hypoxia in mice. Am. J. Physiol. Heart Circ. Physiol. 300 H736–H744
    1. Warrington J. P., Csiszar A., Johnson D. A., Herman T. S., Ahmad S., Lee Y. W., Sonntag W. E. (2011b). Systemic hypoxia reverses whole brain radiation-induced microvascular rarefaction. FASEB J. 25 636
    1. Warrington J. P., Csiszar A., Mitschelen M., Lee Y. W., Sonntag W. E. (2012). Whole brain radiation-induced impairments in learning and memory are time-sensitive and reversible by systemic hypoxia. PLoS ONE 7 e30444 10.1371/journal.pone.0030444
    1. Weitzner M. A., Meyers C. A., Valentine A. D. (1995). Methylphenidate in the treatment of neurobehavioral slowing associated with cancer and cancer treatment. J. Neuropsychiatry Clin. Neurosci. 7 347–350
    1. Welzel G., Fleckenstein K., Schaefer J., Hermann B., Kraus-Tiefenbacher U., Mai S. K., Wenz F. (2008). Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 72 1311–1318
    1. Wilson C. M., Gaber M. W., Sabek O. M., Zawaski J. A., Merchant T. E. (2009). Radiation-induced astrogliosis and blood–brain barrier damage can be abrogated using anti-TNF treatment. Int. J. Radiat. Oncol. Biol. Phys. 74 934–941
    1. Wilson J. X. (1997). Antioxidant defense of the brain: a role for astrocytes. Can. J. Physiol. Pharmacol. 75 1149–1163
    1. Wong-Goodrich S. J. E., Pfau M. L., Flores C. T., Fraser J. A., Williams C. L., Jones L. W. (2010). Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation. Cancer Res. 70 9329–9338
    1. Yazlovitskaya E. M., Edwards E., Thotala D., Fu A., Osusky K. L., Whetsell W. O., Boone B., Shinohara E. T., Hallahan D. E. (2006). Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res. 66 11179–11186
    1. Yoneoka Y., Satoh M., Akiyama K., Sano K., Fujii Y., Tanaka R. (1999). An experimental study of radiation-induced cognitive dysfunction in an adult rat model. Br. J. Radiol. 72 1196–1201
    1. Yousem D. M., Lenkinski R. E., Evans S., Allen D., O’Brien R., Curran W., Schnall M., Bennett M., Wehrli S. L., Grossman R. I. (1992). Proton MR spectroscopy of experimental radiation-induced white matter injury. J. Comput. Assist. Tomogr. 16 543–548
    1. Yuan H., Gaber M. W., Boyd K., Wilson C. M., Kiani M. F., Merchant T. E. (2006). Effects of fractionated radiation on the brain vasculature in a murine model: blood–brain barrier permeability, astrocyte proliferation, and ultrastructural changes. Int. J. Radiat. Oncol. Biol. Phys. 66 860–866
    1. Zhao W., Diz D. I., Robbins M. E. (2007a). Oxidative damage pathways in relation to normal tissue injury. Br. J. Radiol. 80 S23–S31
    1. Zhao W., Payne V., Tommasi E., Diz D. I., Hsu F.-C., Robbins M. E. (2007b). Administration of the peroxisomal proliferator-activated receptor (PPAR)γ agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. Int. J. Radiat. Oncol. Biol. Phys. 67 6–9
    1. Zhou H., Liu Z., Liu J., Wang J., Zhou D., Zhao Z., Xiao S., Tao E., Suo W.Z. (2011) Fractionated radiation-induced acute encephalopathy in a young rat model: cognitive dysfunction and histologic findings. AJNR Am. J. Neuroradiol. 32 1795–800
    1. Zou P., Mulhern R. K., Butler R. W., Li C. S., Langston J. W., Ogg R. J. (2005). BOLD responses to visual stimulation in survivors of childhood cancer. Neuroimage 24 61–69

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera