Skip to main content Accessibility help
×
Hostname: page-component-8448b6f56d-42gr6 Total loading time: 0 Render date: 2024-04-21T09:57:31.976Z Has data issue: false hasContentIssue false

1 - Neuropathology and pathophysiology of stroke

from Section I - Etiology, pathophysiology and imaging

Published online by Cambridge University Press:  05 May 2010

Michael Brainin
Affiliation:
Zentrum für Klinische Neurowissenschaften, Donnau-Universität, Krems, Austria
Wolf-Dieter Heiss
Affiliation:
Universität zu Köln
Get access

Summary

The vascular origin of cerebrovascular disease

All cerebrovascular diseases (CVD) have their origin in the vessels supplying or draining the brain. Therefore, knowledge of pathological changes occurring in the vessels and in the blood is essential for understanding the pathophysiology of the various types of CVD and for the planning of efficient therapeutic strategies. Changes in the vessel wall lead to obstruction of blood flow, by interacting with blood constituents they may cause thrombosis and blockade of blood flow in this vessel. In addition to vascular stenosis or occlusion at the site of vascular changes, disruption of blood supply and consecutive infarcts can also be produced by emboli arising from vascular lesions situated proximally to otherwise healthy branches located more distal in the arterial tree or from a source located in the heart. At the site of occlusion, the opportunity exists for thrombus to develop in anterograde fashion throughout the length of the vessel, but this event seems to occur only rarely.

Changes in large arteries supplying the brain, including the aorta, are mainly caused by atherosclerosis. Middle-sized and intracerebral arteries can also be affected by acute or chronic vascular diseases of inflammatory origin due to subacute to chronic infections, e.g. tuberculosis and lues, or due to collagen disorders, e.g. giant cell arteriitis, granulomatous angiitis of the CNS, panarteritis nodosa, and even more rarely systemic lupus erythematosus, Takayasu's arteriitis, Wegener granulomatosis, rheumatoid arteriitis, Sjögren's syndrome, or Sneddon and Behcet's disease.

Type
Chapter
Information
Publisher: Cambridge University Press
Print publication year: 2009

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

Rajamani, K, Fisher, M, Fisher, M. Atherosclerosis – pathogenesis and pathophysiology. In: Ginsberg, MD, Bogousslavsky, J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis and Management, Vol. 2. London: Blackwell Science; 1998:308–18.Google Scholar
Willeit, J, Kiechl, S. Biology of arterial atheroma. Cerebrovasc Dis (Basel) 2000;10 Suppl 5:1–8.CrossRefGoogle ScholarPubMed
Ross, R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115–26.CrossRefGoogle ScholarPubMed
Aikawa, M, Libby, P. The vulnerable atherosclerotic plaque: pathogenesis and therapeutic approach. Cardiovasc Pathol 2004; 13:125–38.CrossRefGoogle ScholarPubMed
Faxon, DP, Fuster, V, Libby, P, Beckman, JA, Hiatt, WR, Thompson, RW, et al. Atherosclerotic Vascular Disease Conference: Writing Group III: pathophysiology. Circulation 2004; 109:2617–25.CrossRefGoogle ScholarPubMed
Dzau, VJ, Braun-Dullaeus, RC, Sedding, DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nature Med 2002; 8:1249–56.CrossRefGoogle ScholarPubMed
Glagov, S, Weisenberg, E, Zarins, CK, Stankunavicius, R, Kolettis, GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316:1371–5.CrossRefGoogle ScholarPubMed
Rauch, U, Osende, JI, Fuster, V, Badimon, JJ, Fayad, Z, Chesebro, JH. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med 2001; 134:224–38.CrossRefGoogle ScholarPubMed
Loscalzo, J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res 2001; 88:756–62.CrossRefGoogle ScholarPubMed
Fisher, CM. Cerebral miliary aneurysms in hypertension. Am J Pathol 1972; 66:313–30.Google ScholarPubMed
Rossrussell, RW. Observations on intracerebral aneurysms. Brain 1963; 86:425–42.CrossRefGoogle ScholarPubMed
Zülch, K-J. Über die Entstehung und Lokalisation der Hirninfarkte. Zentralbl Neurochir 1961; 21:158–78.Google Scholar
Zülch, K-J. The Cerebral Infarct. Pathology, Pathogenesis, and Computed Tomography. Berlin: Springer-Verlag; 1985.CrossRefGoogle Scholar
Mohr, JP, Choi, DW, Grotta, JC, Weir, B, Wolf, PA. Stroke – Pathophysiology, Diagnosis, and Management. 4th ed. Philadelphia: Churchill Livingstone; 2004.Google Scholar
Wolf, PA. Epidemiology of stroke. In: Mohr, JP, Choi, DW, Grotta, JC, Weir, B, Wolf, PA, eds. Stroke – Pathophysiology, Diagnosis, and Management. Philadelphia: Churchill Livingstone; 2004: 13–34.Google Scholar
Stochdorph, O. Der Mythos der letzten Wiese. Zentralbl Allg Pathol Path Anat 1977; 121:554.Google Scholar
Ringelstein, EB, Zunker, P. Low-flow infarction. In: Ginsberg, MD, Bogousslavsky, J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management, Vol. 2. London: Blackwell Science; 1998: 1075–89.Google Scholar
Fisher, CM. Lacunes: small, deep cerebral infarcts. Neurology 1965; 15:774–84.CrossRefGoogle ScholarPubMed
Beghi, E, Bogliun, G, Cavaletti, G, Sanguineti, I, Tagliabue, M, Agostoni, F, et al. Hemorrhagic infarction: risk factors, clinical and tomographic features, and outcome. A case-control study. Acta Neurol Scand 1989; 80:226–31.CrossRefGoogle ScholarPubMed
Lodder, J, Krijne-Kubat, B, Broekman, J. Cerebral hemorrhagic infarction at autopsy: cardiac embolic cause and the relationship to the cause of death. Stroke 1986; 17:626–9.CrossRefGoogle ScholarPubMed
Fisher, M, Adams, RD. Observations on brain embolism with special reference to the mechanism of hemorrhagic infarction. J Neuropathol Exp Neurol 1951; 10:92–4.Google ScholarPubMed
Mohr, JP, Caplan, LR, Melski, JW, Goldstein, RJ, Duncan, GW, Kistler, JP, et al. The Harvard Cooperative Stroke Registry: A prospective registry. Neurology 1978; 28:754–62.CrossRefGoogle ScholarPubMed
Sacco, RL, Wolf, PA, Bharucha, NE, Meeks, SL, Kannel, WB, Charette, LJ, et al. Subarachnoid and intracerebral hemorrhage: natural history, prognosis, and precursive factors in the Framingham Study. Neurology 1984; 34:847–54.CrossRefGoogle ScholarPubMed
Feldman, E. Intracerebral Hemorrhage. Armonk, NY: Futura; 1994.Google Scholar
Schütz, H. Spontane intrazerebrale Hämatome. Pathophysiologie, Klinik und Therapie. Berlin: Springer-Verlag; 1988.CrossRefGoogle Scholar
Kase, CS, Mohr, JP, Caplan, LR. Intracerebral Hemorrhage. In: Mohr, JP, Choi, DW, Grotta, JC, Weir, B, Wolf, PA, eds. Stroke – Pathophysiology, Diagnosis, and Management. Philadelphia: Churchill Livingstone; 2004: 327–76.Google Scholar
Fisher, CM. Pathological observations in hypertensive cerebral hemorrhage. J Neuropathol Exp Neurol 1971; 30:536–50.CrossRefGoogle ScholarPubMed
Brott, T, Broderick, J, Kothari, R, Barsan, W, Tomsick, T, Sauerbeck, L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28:1–5.CrossRefGoogle ScholarPubMed
Gonzalez-Duarte, A, Cantu, C, Ruiz-Sandoval, JL, Barinagarrementeria, F. Recurrent primary cerebral hemorrhage: frequency, mechanisms, and prognosis. Stroke 1998; 29:1802–5.CrossRefGoogle ScholarPubMed
Bousser, MG, Barnett, HJM. Cerebral venous thrombosis. In: Mohr, JP, Choi, DW, Grotta, JC, Weir, B, Wolf, PA, eds. Stroke – Pathophysiology, Diagnosis, and Management, 4th ed. Philadelphia: Churchill Livingstone; 2004: 301–25.Google Scholar
Auer, RN, Benveniste, H (eds). Hypoxia and Related Conditions. London: Arnold; 1997: 283–98.
Petito, CK (ed). The Neuropathology of Focal Brain Ischemia. Basel: ISN Neuropath Press; 2005: 215–21.
Brown, AW, Brierley, JB. Anoxic-ischaemic cell change in rat brain. Light microscopic and fine-structural observations. J Neurol Sci 1972; 16:59–84.CrossRefGoogle ScholarPubMed
Kirino, T, Sano, K. Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol 1984; 62:201–8.CrossRefGoogle ScholarPubMed
Martin, LJ. The apoptosis-necrosis cell death continuum in CNS development, injury and disease: contributions and mechanisms. In: Lo EH, , Marwah, J, eds. Neuroprotection. Scotsdale, AZ: Prominent Press; 2001: 378–412.Google Scholar
Charriaut-Marlangue, C, Benari, Y. A cautionary note on the use of the TUNEL stain to determine apoptosis. NeuroReport 1995; 7:61–4.CrossRefGoogle ScholarPubMed
Hossmann, K-A. Disturbances of cerebral protein synthesis and ischemic cell death. Prog Brain Res 1993; 96:161–77.CrossRefGoogle ScholarPubMed
DeGracia, DJ, Rafols, JA, Morley, SJ, Kayali, F. Immunohistochemical mapping of total and phosphorylated eukaryotic initiation factor 4G in rat hippocampus following global brain ischemia and reperfusion. Neuroscience 2006; 139:1235–48.CrossRefGoogle ScholarPubMed
Hudgins, WR, Garcia, JH. Transorbital approach to the middle cerebral artery of the squirrel monkey: a technique for experimental cerebral infarction applicable to ultrastructural studies. Stroke 1970; 1:107–11.CrossRefGoogle ScholarPubMed
Tamura, A, Graham, DI, McCulloch, J, Teasdale, GM. Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1981; 1:53–60.CrossRefGoogle ScholarPubMed
Koizumi, J, Yoshida, Y, Nakazawa, T, Ooneda, G. Experimental studies of ischemic brain edema. 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 1986; 8:1–8.CrossRefGoogle Scholar
Rogers, DC, Campbell, CA, Stretton, JL, Mackay, KB. Correlation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke 1997; 28:2060–5.CrossRefGoogle ScholarPubMed
DiNapoli, VA, Rosen, CL, Nagamine, T, Crocco, T. Selective MCA occlusion: A precise embolic stroke model. J Neurosci Methods 2006; 154:233–8.CrossRefGoogle ScholarPubMed
Orset, C, Macrez, R, Young, AR, Panthou, D, Angles-Cano, E, Maubert, E, et al. Mouse model of in situ thromboembolic stroke and reperfusion. Stroke 2007; 38:2771–8.CrossRefGoogle ScholarPubMed
Chen, F, Suzuki, Y, Nagai, N, Jin, LX, Yu, J, Wang, HJ, et al. Rodent stroke induced by photochemical occlusion of proximal middle cerebral artery: evolution monitored with MR imaging and histopathology. Eur J Radiol 2007; 63:68–75.CrossRefGoogle ScholarPubMed
Symon, L. Regional vascular reactivity in the middle cerebral arterial distribution. An experimental study in baboons. J Neurosurg 1970; 33:532–41.CrossRefGoogle ScholarPubMed
Hata, R, Maeda, K, Hermann, D, Mies, G, Hossmann, K-A. Evolution of brain infarction after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 2000; 20:937–46.CrossRefGoogle ScholarPubMed
Toole, JF, McGraw, CP. The steal syndromes. Annu Rev Med 1975; 26:321–9.CrossRefGoogle ScholarPubMed
Pakkenberg, B, Gundersen, HJ. Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 1997; 384:312–20.3.0.CO;2-K>CrossRefGoogle ScholarPubMed
Clarke, DD, Sokoloff, L. Circulation and energy metabolism of the brain. In: Siegel, G, Agranoff, B, Albers, RW, Fisher, S, eds. Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 6th ed. Philadelphia: Lippincott-Raven; 1999: 637–69.Google Scholar
Sokoloff, L. Energetics of functional activation in neural tissues. Neurochem Res 1999; 24:321–9.CrossRefGoogle ScholarPubMed
Magistretti, PJ, Pellerin, L. Astrocytes couple synaptic activity to glucose utilization in the brain. News Physiol Sci 1999; 14:177–82.Google Scholar
Laughlin, SB, Attwell, D. The metabolic cost of neural information: from fly eye to mammalian cortex. In: Frackowiak, RSJ, Magistretti, PJ, Shulman, RG, Altman, JS, Adams, M, eds. Neuroenergetics: Relevance for Functional Brain Imaging. Strasbourg: HFSP Workshop XI, 2001; 54–64.Google Scholar
Frackowiak, RSJ, Magistretti, PJ, Shulman, RG, Altman, JS, Adams, M (eds). Neuroenergetics: Relevance for Functional Brain Imaging. Strasbourg: HFSP Workshop XI, 2001.
Astrup, J, Siesjö, BK, Symon, L. Thresholds in cerebral ischemia – the ischemic penumbra. Stroke 1981; 12:723–5.CrossRefGoogle ScholarPubMed
Heiss, WD. Experimental evidence of ischemic thresholds and functional recovery. Stroke 1992; 23:1668–72.CrossRefGoogle ScholarPubMed
Hossmann, KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994; 36:557–65.CrossRefGoogle ScholarPubMed
Kirino, T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 1982; 239:57–69.CrossRefGoogle ScholarPubMed
Hossmann, K-A, Mies, G (eds). Multimodal Mapping of the Ischemic Penumbra in Animal Models. New York: Marcel Dekker; 2007: 77–92.
Hata, R, Maeda, K, Hermann, D, Mies, G, Hossmann, K-A. Dynamics of regional brain metabolism and gene expression after middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 2000; 20:306–15.CrossRefGoogle ScholarPubMed
Heiss, WD. Ischemic penumbra: evidence from functional imaging in man [Review]. J Cereb Blood Flow Metab 2000; 20:1276–93.CrossRefGoogle Scholar
Takasawa, M, Beech, JS, Fryer, TD, Hong, YT, Hughes, JL, Igase, K, et al. Imaging of brain hypoxia in permanent and temporary middle cerebral artery occlusion in the rat using F-18-fluoromisonidazole and positron emission tomography: a pilot study. J Cereb Blood Flow Metab 2007; 27:679–89.CrossRefGoogle ScholarPubMed
Kane, I, Sandercock, P, Wardlaw, J. Magnetic resonance perfusion diffusion mismatch and thrombolysis in acute ischaemic stroke: a systematic review of the evidence to date. J Neurol Neurosurg Psychiatry 2007; 78:485–90.CrossRefGoogle ScholarPubMed
Hoehn-Berlage, M, Norris, DG, Kohno, K, Mies, G, Leibfritz, D, Hossmann, K-A. Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. J Cereb Blood Flow Metab 1995; 15:1002–11.CrossRefGoogle ScholarPubMed
Sun, PZ, Zhou, JY, Sun, WY, Huang, J, Zijl, PCM. Detection of the ischemic penumbra using pH-weighted MRI. J Cereb Blood Flow Metab 2007; 27:1129–36.CrossRefGoogle ScholarPubMed
Heckl, S. Future contrast agents for molecular imaging in stroke. Curr Med Chem 2007; 14:1713–28.CrossRefGoogle ScholarPubMed
Strong, AJ, Anderson, PJ, Watts, HR, Virley, DJ, Lloyd, A, Irving, EA, et al. Peri-infarct depolarizations lead to loss of perfusion in ischaemic gyrencephalic cerebral cortex. Brain 2007; 130:995–1008.CrossRefGoogle ScholarPubMed
Simon, R, Xiong, Z. Acidotoxicity in brain ischaemia. Biochem Soc Trans 2006; 34:1356–61.CrossRefGoogle ScholarPubMed
Choi, DW. Excitotoxic cell-death. J Neurobiol 1992; 23:1261–76.CrossRefGoogle ScholarPubMed
Siesjö, BK. Calcium, excitotoxins, and brain damage. News Physiol Sci 1990; 5:120–5.Google Scholar
MacDonald, JF, Xiong, ZG, Jackson, MF. Paradox of Ca2+signaling, cell death and stroke. Trends Neurosci 2006; 29:75–81.CrossRefGoogle ScholarPubMed
Chan, PH. Role of oxidants in ischemic brain damage. Stroke 1996; 27:1124–9.CrossRefGoogle ScholarPubMed
Shuaib, A, Lees, K, Lyden, P, Grotta, J, Davalos, A, Davis, S, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007; 357:562.CrossRefGoogle ScholarPubMed
Dalkara, T, Moskowitz, MA. The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia. Brain Pathol 1994; 4:49–57.CrossRefGoogle ScholarPubMed
Sensi, SL, Jeng, JM. Rethinking the excitotoxic ionic milieu: the emerging role of Zn2+in ischemic neuronal injury. Curr Mol Med 2004; 4:87–111.CrossRefGoogle ScholarPubMed
Paschen, W. Dependence of vital cell function on endoplasmic reticulum calcium levels: implications for the mechanisms underlying neuronal cell injury in different pathological states [Review]. Cell Calcium 2001; 29:1–11.CrossRefGoogle Scholar
DeGracia, DJ, Hu, BR. Irreversible translation arrest in the reperfused brain. J Cereb Blood Flow Metab 2007; 27:875–93.CrossRefGoogle ScholarPubMed
Norenberg, MD, Rao, KVR. The mitochondrial permeability transition in neurologic disease. Neurochem Int 2007; 50:983–97.CrossRefGoogle ScholarPubMed
Rothwell, NJ, Luheshi, GN. Interleukin I in the brain: biology, pathology and therapeutic target [Review]. Trends Neurosci 2000; 23:618–25.CrossRefGoogle Scholar
Planas, AM, Gorina, R, Chamorro, A. Signalling pathways mediating inflammatory responses in brain ischaemia. Biochem Soc Trans 2006; 34:1267–70.CrossRefGoogle ScholarPubMed
Wang, CX, Shuaib, A. Critical role of microvasculature basal lamina in ischemic brain injury. Prog Neurobiol 2007; 83:140–8.CrossRefGoogle ScholarPubMed
Walz, B, Zimmermann, C, Bottger, S, Haberl, RL. Prognosis of patients after hemicraniectomy in malignant middle cerebral artery infarction. J Neurol 2002; 249:1183–90.CrossRefGoogle ScholarPubMed
Lansberg, MG, Thijs, VN, O'Brien, MW, Ali, JO, Crespigny, AJ, Tong, DC, et al. Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke. Am J Neuroradiol 2001; 22:637–44.Google ScholarPubMed
Badaut, T, Lasbennes, T, Magistretti, PJ, Regli, L. Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab 2002; 22:367–78.CrossRefGoogle ScholarPubMed
Johnson, EM, Greenlund, LJS, Akins, PT, Hsu, CY. Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma 1995; 12:843–52.CrossRefGoogle ScholarPubMed
MacManus, JP, Buchan, AM. Apoptosis after experimental stroke: Fact or fashion? [Review]. J Neurotrauma 2000; 17:899–914.CrossRefGoogle Scholar
Dirnagl, U, Simon, RP, Hallenbeck, JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 2003; 26:248–54.CrossRefGoogle ScholarPubMed
Zhao, H, Sapolsky, RM, Steinberg, GK. Interrupting reperfusion as a stroke therapy: ischemic postconditioning reduces infarct size after focal ischemia in rats. J Cereb Blood Flow Metab 2006; 26:1114–21.CrossRefGoogle ScholarPubMed
Wiltrout, C, Lang, B, Yan, YP, Dempsey, RJ, Vemuganti, R. Repairing brain after stroke: a review on post-ischemic neurogenesis. Neurochem Int 2007; 50:1028–41.CrossRefGoogle ScholarPubMed
Kuhl, , Phelps, ME, Kowell, AP, Metter, EJ, Selin, C, Winter, J. Effects of stroke on local cerebral metabolism and perfusion: Mapping by emission computed tomography of 18 FDG and 13 NH 3. Ann Neurol 1980; 8:47–60.CrossRefGoogle Scholar
Baron, JC, Frackowiak, RS, Herholz, K, Jones, T, Lammertsma, AA, Mazoyer, B, et al. Use of PET methods for measurement of cerebral energy metabolism and hemodynamics in cerebrovascular disease. J Cereb Blood Flow Metab 1989; 9:723–42.CrossRefGoogle ScholarPubMed
Heiss, WD, Grond, M, Thiel, A, Ghaemi, M, Sobesky, J, Rudolf, J, et al. Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke. Stroke 1998; 29:454–61.CrossRefGoogle ScholarPubMed
Sobesky, J, Weber, OZ, Lehnhardt, FG, Hesselmann, V, Neveling, M, Jacobs, A, et al. Does the mismatch match the penumbra? Magnetic resonance imaging and positron emission tomography in early ischemic stroke. Stroke 2005; 36:980–5.CrossRefGoogle ScholarPubMed
Garcia, JH, Liu, KF, Ho, KL. Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 1995; 26:636–42.CrossRefGoogle ScholarPubMed
Magistretti, PJ. Coupling synaptic activity to glucose metabolism. In: Frackowiak, RSJ, Magistretti, PJ, Shulman, RG, Altman, JS, Adams, M, eds. Neuroenergetics: Relevance for Functional Brain Imaging. Strasbourg: HFSP Workshop XI, 2001: 133–42.Google Scholar
Attwell, D, Laughlin, SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 2001; 21:1133–45.CrossRefGoogle Scholar

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
×