Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-8448b6f56d-dnltx Total loading time: 0 Render date: 2024-04-25T05:01:37.626Z Has data issue: false hasContentIssue false

Chapter 10 - Neuroimaging Brain Inflammation in Mood Disorders

from Section 3 - Functional and Neurochemical Brain Studies

Published online by Cambridge University Press:  12 January 2021

By
Jeffrey H. Meyer
Edited by
Sudhakar Selvaraj ,
Paolo Brambilla  and
Jair C. Soares
Sudhakar Selvaraj
Affiliation:
UTHealth School of Medicine, USA
Paolo Brambilla
Affiliation:
Università degli Studi di Milano
Jair C. Soares
Affiliation:
UT Harris County Psychiatric Center, USA
Get access

Summary

Neuroimaging with positron emission tomography is increasingly developing radioligands that emulate targets traditionally within the domain of postmortem studies. Consequently, markers indicative of neuroinflammatory processes are advancing and enabling rapid assessment of the neuroinflammatory theory of major depressive disorder (MDD). One marker, translocator protein (TSPO), has now had a significant number of investigations in MDD and it is anticipated that investigations of other neuroinflammatory markers will be extended into mood disorders. Of these measures, neuroimaging of monoamine oxidase B demonstrates promising differences between MDD and health.

Type
Chapter
Information
Mood Disorders
Brain Imaging and Therapeutic Implications
 , pp. 121 - 134
Publisher: Cambridge University Press
Print publication year: 2021

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Miller, AH, Maletic, V, Raison, CL. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009; 65(9): 732–741.CrossRefGoogle ScholarPubMed
Dowlati, Y, Herrmann, N, Swardfager, W, et al. A meta-analysis of Cytokines in major depression. Biol Psychiatry. 2010 March 1; 67(5): 446–457.CrossRefGoogle ScholarPubMed
Musselman, DL, Lawson, DH, Gumnick, JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001; 344(13): 961–966.CrossRefGoogle ScholarPubMed
Capuron, L, Gumnick, JF, Musselman, DL, et al. Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002; 26(5): 643–652.CrossRefGoogle ScholarPubMed
Brydon, L, Harrison, NA, Walker, C, Steptoe, A, Critchley, HD. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry. 2008; 63(11): 1022–1029.CrossRefGoogle ScholarPubMed
Reichenberg, A, Yirmiya, R, Schuld, A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001; 58(5): 445–452.Google Scholar
Salazar, A, Gonzalez-Rivera, BL, Redus, L, Parrott, JM, O’Connor, JC. Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge. Horm Behav. 2012; 62(3): 202–209.CrossRefGoogle ScholarPubMed
Yang, L, Wang, M, et al. Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway. Brain Behav Immun. 2016; 56: 352–362.CrossRefGoogle ScholarPubMed
Yu, I, Inaji, M, Maeda, J, et al. Glial cell-mediated deterioration and repair of the nervous system after traumatic brain injury in a rat model as assessed by positron emission tomography. J Neurotrauma. 2010; 27(8): 1463–1475.CrossRefGoogle Scholar
Grossman, R, Paden, CM, Fry, PA, Rhodes, RS, Biegon, A. Persistent region-dependent neuroinflammation, NMDA receptor loss and atrophy in an animal model of penetrating brain injury. Future Neurol. 2012; 7(3): 329–339.Google Scholar
Raghavendra Rao, VL, Dogan, A, Bowen, KK, Dempsey, RJ. Traumatic brain injury leads to increased expression of peripheral-type benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus. Exp Neurol. 2000; 161(1): 102–114.CrossRefGoogle ScholarPubMed
Ramlackhansingh, AF, Brooks, DJ, Greenwood, RJ,et al. Inflammation after trauma: Microglial activation and traumatic brain injury. Ann Neurol. 2011; 70(3): 374–383.CrossRefGoogle ScholarPubMed
Rapoport, MJ. Depression following traumatic brain injury: epidemiology, risk factors and management. CNS Drugs. 2012; 26(2): 111–121.CrossRefGoogle ScholarPubMed
Bombardier, CH, Fann, JR, Temkin, NR, Et al. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA. 2010; 303(19): 1938–1945.CrossRefGoogle ScholarPubMed
Jorge, RE, Robinson, RG, Moser, D, et al. Major depression following traumatic brain injury. Arch Gen Psychiatry. 2004; 61(1): 42–50.Google Scholar
Brey, RL, Holliday, SL, Saklad, AR, et al. Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology. 2002; 58(8): 1214–1220.CrossRefGoogle ScholarPubMed
Nery, FG, Borba, EF, Viana, VS, et al. Prevalence of depressive and anxiety disorders in systemic lupus erythematosus and their association with anti-ribosomal P antibodies. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(3): 695–700.CrossRefGoogle ScholarPubMed
Bachen, EA, Chesney, MA, Criswell, LA. Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus. Arthritis Rheum. 2009; 61(6): 822–829.CrossRefGoogle ScholarPubMed
Minden, SL, Orav, J, Reich, P. Depression in multiple sclerosis. Gen Hosp Psychiatry. 1987; 9(6): 426–434.CrossRefGoogle ScholarPubMed
Sadovnick, AD, Eisen, K, Ebers, GC, Paty, DW. Cause of death in patients attending multiple sclerosis clinics. Neurology. 1991; 41(8): 1193–1196.CrossRefGoogle ScholarPubMed
Joffe, RT, Lippert, GP, Gray, TA, Sawa, G, Horvath, Z. Mood disorder and multiple sclerosis. Arch Neurol. 1987; 44(4): 376–378.CrossRefGoogle ScholarPubMed
Pandey, GN, Rizavi, HS, Ren, X, et al. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J Psychiatr Res. 2012; 46(1): 57–63.CrossRefGoogle ScholarPubMed
Shelton, RC, Claiborne, J, Sidoryk-Wegrzynowicz, M, et al. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry. 2011; 16(7): 751–762.CrossRefGoogle ScholarPubMed
Steiner, J, Bielau, H, Brisch, R, et al. Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2008; 42(2): 151–157.CrossRefGoogle ScholarPubMed
Mahajan, GJ, Vallender, EJ, Garrett, MR, et al. Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2018; 82: 177–186.Google Scholar
Kreutzberg, GW. Microglia: A sensor for pathological events in the CNS. Trends in Neurosciences. 1996; 19(8): 312–318.Google Scholar
Carbonell, WS, Murase, S, Horwitz, AF, Mandell, JW. Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5: An in situ time-lapse confocal imaging study. J Neurosci. 2005; 25(30): 7040–7047.CrossRefGoogle Scholar
Cross, AK, Woodroofe, MN. Chemokines induce migration and changes in actin polymerization in adult rat brain microglia and a human fetal microglial cell line in vitro. J Neurosci Res. 1999; 55(1): 17–23.Google Scholar
Gehrmann, J, Matsumoto, Y, Kreutzberg, GW. Microglia: Intrinsic immuneffector cell of the brain. Brain Research Reviews. 1995; 20(3): 269–287.CrossRefGoogle ScholarPubMed
Dantzer, R, O’Connor, JC, Freund, GG, Johnson, RW, Kelley, KW. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat Rev Neurosci. 2008; 9(1): 46–56.CrossRefGoogle ScholarPubMed
Wohleb, ES, Franklin, T, Iwata, M, Duman, RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016; 17(8): 497–511.CrossRefGoogle ScholarPubMed
Venneti, S, Wiley, CA, Kofler, J. Imaging microglial activation during neuroinflammation and Alzheimer’s disease. J Neuroimmune Pharmacol. 2009; 4(2): 227–243.CrossRefGoogle ScholarPubMed
Banati, RB, Myers, R, Kreutzberg, GW. PK (‘peripheral benzodiazepine’)–binding sites in the CNS indicate early and discrete brain lesions: Microautoradiographic detection of [3 H]PK11195 binding to activated microglia. J Neurocytol. 1997; 26(2): 77–82.CrossRefGoogle ScholarPubMed
Martin, A, Boisgard, R, Theze, B, et al. Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2010; 30(1): 230–241.CrossRefGoogle Scholar
Hannestad, J, Dellagioia, N, Gallezot, JD, et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: A [C]PBR28 PET study. Brain Behav Immun. 2013; 33: 131–138.CrossRefGoogle Scholar
Betlazar, C, Harrison-Brown, M, Middleton, RJ, Banati, R, Liu, GJ. Cellular sources and regional variations in the expression of the neuroinflammatory marker translocator protein (TSPO) in the normal brain. Int J Mol Sci. 2018 September 11; 19(9): 2707.CrossRefGoogle ScholarPubMed
Cosenza-Nashat, M, Zhao, ML, Suh, HS, et al. Expression of the translocator protein of 18kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathology and Applied Neurobiology. 2009; 35(3): 306–328.Google Scholar
Kropholler, MA, Boellaard, R, Schuitemaker, A, et al. Evaluation of reference tissue models for the analysis of [11 C](R)-PK11195 studies. J Cereb Blood Flow Metab. 2006; 26(11): 1431–1441.CrossRefGoogle ScholarPubMed
Imaizumi, M, Kim, HJ, Zoghbi, SS, et al. PET imaging with [11 C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci Lett. 2007; 411(3): 200–205.CrossRefGoogle ScholarPubMed
Wilson, AA, Garcia, A, Parkes, J, et al. Radiosynthesis and initial evaluation of [18 F]-FEPPA for PET imaging of peripheral benzodiazepine receptors. Nucl Med Biol. 2008; 35(3): 305–314.CrossRefGoogle ScholarPubMed
Ikawa, M, Lohith, TG, Shrestha, S, et al. Biomarkers consortium radioligand project T. 11 C-ER176, a radioligand for 18-kDa translocator protein, has adequate sensitivity to robustly image all three affinity genotypes in human brain. J Nucl Med. 2017; 58(2): 320–325.CrossRefGoogle Scholar
Wimberley, C, Lavisse, S, Brulon, V, et al. Impact of endothelial 18-kDa translocator protein on the quantification of (18)F-DPA-714. J Nucl Med. 2018; 59(2): 307–314.CrossRefGoogle ScholarPubMed
Medran-Navarrete, V, Damont, A, Peyronneau, MA, et al. Preparation and evaluation of novel pyrazolo[1,5-a]pyrimidine acetamides, closely related to DPA-714, as potent ligands for imaging the TSPO 18kDa with PET. Bioorg Med Chem Lett. 2014; 24(6): 1550–1556.CrossRefGoogle Scholar
Fookes, CJ, Pham, TQ, Mattner, F, et al. Synthesis and biological evaluation of substituted [18 F]imidazo[1,2-a]pyridines and [18 F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography. J Med Chem. 2008; 51(13): 3700–3712.CrossRefGoogle Scholar
James, ML, Fulton, RR, Vercoullie, J, et al. DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med. 2008; 49(5): 814–822.CrossRefGoogle ScholarPubMed
Zanotti-Fregonara, P, Zhang, Y, Jenko, KJ, et al. Synthesis and evaluation of translocator 18 kDa protein (TSPO) positron emission tomography (PET) radioligands with low binding sensitivity to human single nucleotide polymorphism rs6971. ACS Chem Neurosci. 2014; 5(10): 963–971.CrossRefGoogle ScholarPubMed
Fujita, M, Imaizumi, M, Zoghbi, SS, et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage. 2008; 40(1): 43–52.Google Scholar
Rusjan, P, Wilson, AA, Bloomfield, PM, et al. Quantification of translocator protein (18kDa) in the human brain with PET and a novel radioligand, [18 F]-FEPPA. JCBFM. 2010; 31(8): 1807–1816.Google Scholar
Guo, Q, Colasanti, A, Owen, DR, et al. Quantification of the specific translocator protein signal of 18 F-PBR111 in healthy humans: A genetic polymorphism effect on in vivo binding. J Nucl Med. 2013; 54(11): 1915–1923.CrossRefGoogle ScholarPubMed
Jucaite, A, Cselenyi, Z, Arvidsson, A, et al. Kinetic analysis and test-retest variability of the radioligand [11 C](R)-PK11195 binding to TSPO in the human brain – a PET study in control subjects. EJNMMI Res. 2012; 2: 15.CrossRefGoogle Scholar
Hagens, MHJ, Golla, SV, Wijburg, MT, et al. In vivo assessment of neuroinflammation in progressive multiple sclerosis: A proof of concept study with [(18)F]DPA714 PET. J Neuroinflammation. 2018; 15(1): 314.CrossRefGoogle Scholar
Collste, K, Forsberg, A, Varrone, A, et al. Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control subjects. Eur J Nucl Med Mol Imaging. 2016; 43(1): 173–183.CrossRefGoogle Scholar
Hashimoto, K, Inoue, O, Suzuki, K, Yamasaki, T, Kojima, M. Synthesis and evaluation of 11 C-PK 11195 for in vivo study of peripheral-type benzodiazepine receptors using positron emission tomography. Ann Nucl Med. 1989; 3(2): 63–71.CrossRefGoogle Scholar
Vicidomini, C, Panico, M, Greco, A, et al. In vivo imaging and characterization of [(18)F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET. Nucl Med Biol. 2015; 42(3): 309–316.CrossRefGoogle ScholarPubMed
Meyer, J. Novel phenotypes detectable with PET in mood disorders: Elevated monoamine oxidase A and translocator protein level. In: Vasdev, N, Alavi, A, editors. PET Clinics: Novel PET Radiotracers with Potential Clinical Applications. Vol 12. United States: Elsevier; 2017, pp. 361–371.Google Scholar
Setiawan, E, Wilson, AA, Mizrahi, R, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015; 72(3): 268–275.CrossRefGoogle ScholarPubMed
Li, H, Sagar, AP, Keri, S. Translocator protein (18kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy. Prog Neuropsychopharmacol Biol Psychiatry. 2018; 83: 1–7.CrossRefGoogle Scholar
Holmes, SE, Hinz, R, Conen, S, et al. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: A positron emission tomography study. Biol Psychiatry. 2018; 83(1): 61–69.CrossRefGoogle Scholar
Setiawan, E, Attwells, S, Wilson, AA, et al. Association of translocator protein total distribution volume with duration of untreated major depressive disorder: A cross-sectional study. Lancet Psychiatry. 2018; 5(4): 339–347.CrossRefGoogle ScholarPubMed
Richards, EM, Zanotti-Fregonara, P, Fujita, M, et al. PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects. EJNMMI Res. 2018; 8(1): 57.CrossRefGoogle ScholarPubMed
Li, H, Sagar, AP, Keri, S. Microglial markers in the frontal cortex are related to cognitive dysfunctions in major depressive disorder. J Affect Disord. 2018; 241: 305–310.CrossRefGoogle ScholarPubMed
Narayanaswami, V, Dahl, K, Bernard-Gauthier, V, et al. Emerging PET radiotracers and targets for imaging of neuroinflammation in neurodegenerative diseases: Outlook beyond TSPO. Mol Imaging. 2018; 17: 1536012118792317.CrossRefGoogle ScholarPubMed
Fowler, JS, MacGregor, RR, Wolf, AP, et al. Mapping human brain monoamine oxidase A and B with 11 C-labeled suicide inactivators and PET. Science. 1987; 235(4787): 481–485.CrossRefGoogle Scholar
Fowler, JS, Wang, GJ, Logan, J, et al. Selective reduction of radiotracer trapping by deuterium substitution: Comparison of carbon-11-L-deprenyl and carbon-11-deprenyl-D2 for MAO B mapping. J Nucl Med. 1995; 36(7): 1255–1262.Google Scholar
Nag, S, Fazio, P, Lehmann, L, et al. In vivo and in vitro characterization of a novel MAO-B inhibitor radioligand, 18 F-labeled deuterated fluorodeprenyl. J Nucl Med. 2016; 57(2): 315–320.Google Scholar
Bramoulle, Y, Puech, F, Saba, W, et al. Radiosynthesis of (S)‐5‐methoxymethyl‐3‐[6‐(4, 4, 4‐trifluorobutoxy) benzo [d] isoxazol‐3‐yl] oxazolidin‐2‐[11 C] one ([11 C] SL25. 1188), a novel radioligand for imaging monoamine oxidase‐B with PET. Journal of Labelled Compounds and Radiopharmaceuticals. 2008; 51(3): 153–158.CrossRefGoogle Scholar
Saba, W, Valette, H, Peyronneau, MA, et al. [(11)C]SL25.1188, a new reversible radioligand to study the monoamine oxidase type B with PET: Preclinical characterisation in nonhuman primate. Synapse. 2010; 64(1): 61–69.CrossRefGoogle Scholar
Vasdev, N, Sadovski, O, Garcia, A, et al. Radiosynthesis of [11 C] SL25. 1188 via [11 C] CO2 fixation for imaging monoamine oxidase B. Journal of Labelled Compounds and Radiopharmaceuticals. 2011; 54(10): 678–680.CrossRefGoogle Scholar
Vasdev, N, Sadovski, O, Moran, MD, et al. Development of new radiopharmaceuticals for imaging monoamine oxidase B. Nucl Med Biol. 2011; 38(7): 933–943.CrossRefGoogle ScholarPubMed
Rusjan, PM, Wilson, AA, Miler, L, et al. Kinetic modeling of the monoamine oxidase B radioligand [(1)(1)C]SL25.1188 in human brain with high-resolution positron emission tomography. J Cereb Blood Flow Metab. 2014; 34(5): 883–889.CrossRefGoogle Scholar
Moriguchi, S, Wilson, AA, Miler, L, et al. Monoamine oxidase B total distribution volume in the prefrontal cortex of major depressive disorder: An [11 C]SL25.1188 positron emission tomography study. JAMA Psychiatry. 2019 June 1; 6(6): 634–641.CrossRefGoogle Scholar
Saura, J, Andres, N, Andrade, C, et al. Biphasic and region-specific MAO-B response to aging in normal human brain. Neurobiol Aging. 1997; 18(5): 497–507.Google Scholar
Tong, J, Jeffrey H. Meyer , Furukawa, Y, Et al. Distribution of monoamine oxidase proteins in human brain: Implications for brain imaging studies. J Cereb Blood Flow Metab. 2013; 33(6): 863–871.CrossRefGoogle ScholarPubMed
Saura, J, Luque, JM, Cesura, AM, et al. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience. 1994; 62(1): 15–30.CrossRefGoogle ScholarPubMed
Ekblom, J, Jossan, SS, Oreland, L, Walum, E, Aquilonius, SM. Reactive gliosis and monoamine oxidase B. J Neural Transm Suppl. 1994; 41: 253–258.Google Scholar
Tong, J, Rathitharan, G, Meyer, Jeffrey H., et al. Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders. Brain. 2017; 140(9): 2460–2474.CrossRefGoogle Scholar
Gulyas, B, Pavlova, E, Kasa, P, et al. Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11 C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int. 2011; 58(1): 60–68.CrossRefGoogle ScholarPubMed
Rajkowska, G, Miguel-Hidalgo, JJ, Wei, J, et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999; 45(9): 1085–1098.CrossRefGoogle ScholarPubMed
Ongur, D, Drevets, WC, Price, JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998; 95(22): 13290–13295.CrossRefGoogle ScholarPubMed
Rajkowska, G, Stockmeier, CA. Astrocyte pathology in major depressive disorder: Insights from human postmortem brain tissue. Curr Drug Targets. 2013; 14(11): 1225–1236.CrossRefGoogle ScholarPubMed
Khundakar, A, Morris, C, Oakley, A, Thomas, AJ. A morphometric examination of neuronal and glial cell pathology in the orbitofrontal cortex in late-life depression. Int Psychogeriatr. 2011; 23(1): 132–140.CrossRefGoogle ScholarPubMed
Si, X, Miguel-Hidalgo, JJ, O’Dwyer, G, Stockmeier, CA, Rajkowska, G. Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology. 2004; 29(11): 2088–2096.CrossRefGoogle ScholarPubMed
Miguel-Hidalgo, JJ, Baucom, C, Dilley, G, et al. Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol Psychiatry. 2000; 48(8): 861–873.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×