Background: Iron accumulation has been linked to neuronal injury following cerebral ischemia. In animals, a hypointense signal on T2*-weighted (T2*-w) MRI correlated with iron deposits in remote brain regions following ischemic stroke. We aim to assess whether such signal changes are present in remote brain structures following ischemic stroke in humans. Methods: We analyzed T2*-w images of 36 patients with unilateral ischemic stroke and 36 healthy controls. Regions of interest (ROIs) consisted of the thalamus, putamen, globus pallidus, caudate nucleus and white matter. To quantify signal intensity in ROIs ipsilateral to the infarct, signal intensity was measured in the ROIs in both hemispheres and a ratio of signal intensity was calculated. Signal asymmetry was compared between patients and controls and its relation with time after stroke onset was assessed. Results: In 34 (94%) patients, the thalamus ipsilateral to the infarct was hypointense compared to the contralateral thalamus. Ipsilateral thalamic signal hypointensity was significantly different between patients and controls (p < 0.001) and was present as early as 1 day after stroke onset. In other ROIs, no difference was found between patients and controls. No association was found between intensity asymmetry and time. Conclusion: We demonstrated that, as early as days after ischemic stroke, T2*-w signal intensity was decreased in the ipsilateral thalamus. This finding might indicate pathophysiologic changes in regions outside the infarcted area, possibly reflecting toxic iron accumulation.

1.
Selim MH, Ratan RR: The role of iron neurotoxicity in ischemic stroke. Ageing Res Rev 2004;3:345-353.
2.
Kell DB: Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med Genomics 2009;2:2.
3.
Castillo J, Leira R: Predictors of deteriorating cerebral infarct: role of inflammatory mechanisms. Would its early treatment be useful? Cerebrovasc Dis 2001;11(suppl 1):40-48.
4.
Moos T, Morgan EH: The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann N Y Acad Sci 2004;1012:14-26.
5.
Lipscomb DC, Gorman LG, Traystman RJ, Hurn PD: Low molecular weight iron in cerebral ischemic acidosis in vivo. Stroke 1998;29:487-492; discussion 493.
6.
Ding H, Yan CZ, Shi H, Zhao YS, Chang SY, Yu P, Wu WS, Zhao CY, Chang YZ, Duan XL: Hepcidin is involved in iron regulation in the ischemic brain. PLoS One 2011;6:e25324.
7.
Chi SI, Wang CK, Chen JJ, Chau LY, Lin TN: Differential regulation of H- and L-ferritin messenger RNA subunits, ferritin protein and iron following focal cerebral ischemia-reperfusion. Neuroscience 2000;100:475-484.
8.
Millerot-Serrurot E, Bertrand N, Mossiat C, Faure P, Prigent-Tessier A, Garnier P, Bejot Y, Giroud M, Beley A, Marie C: Temporal changes in free iron levels after brain ischemia relevance to the timing of iron chelation therapy in stroke. Neurochem Int 2008;52:1442-1448.
9.
Dávalos A, Castillo J, Marrugat J, Fernandez-Real JM, Armengou A, Cacabelos P, Rama R: Body iron stores and early neurologic deterioration in acute cerebral infarction. Neurology 2000;54:1568-1574.
10.
Haacke EM, Miao Y, Liu M, Habib CA, Katkuri Y, Liu T, Yang Z, Lang Z, Hu J, Wu J: Correlation of putative iron content as represented by changes in R2* and phase with age in deep gray matter of healthy adults. J Magn Reson Imaging 2010;32:561-576.
11.
Langkammer C, Krebs N, Goessler W, Scheurer E, Ebner F, Yen K, Fazekas F, Ropele S: Quantitative MR imaging of brain iron: a postmortem validation study. Radiology 2010;257:455-462.
12.
Hermier M, Nighoghossian N: Contribution of susceptibility-weighted imaging to acute stroke assessment. Stroke 2004;35:1989-1994.
13.
Mittal S, Wu Z, Neelavalli J, Haacke EM: Susceptibility-weighted imaging: technical aspects and clinical applications, part 2. AJNR Am J Neuroradiol 2009;30:232-252.
14.
Tang MY, Chen TW, Zhang XM, Huang XH: GRE T2*-weighted MRI: principles and clinical applications. Biomed Res Int 2014;2014:312142.
15.
Freret T, Chazalviel L, Roussel S, Bernaudin M, Schumann-Bard P, Boulouard M: Long-term functional outcome following transient middle cerebral artery occlusion in the rat: correlation between brain damage and behavioral impairment. Behav Neurosci 2006;120:1285-1298.
16.
Hirouchi Y, Suzuki E, Mitsuoka C, Jin H, Kitajima S, Kohjimoto Y, Enomoto M, Kugino K: Neuroimaging and histopathological evaluation of delayed neurological damage produced by artificial occlusion of the middle cerebral artery in Cynomolgus monkeys: establishment of a monkey model for delayed cerebral ischemia. Exp Toxicol Pathol 2007;59:9-16.
17.
Iizuka H, Sakatani K, Young W: Neural damage in the rat thalamus after cortical infarcts. Stroke 1990;21:790-794.
18.
Abe O, Nakane M, Aoki S, Hayashi N, Masumoto T, Kunimatsu A, Mori H, Tamura A, Ohtomo K: MR imaging of postischemic neuronal death in the substantia nigra and thalamus following middle cerebral artery occlusion in rats. NMR Biomed 2003;16:152-159.
19.
Justicia C, Ramos-Cabrer P, Hoehn M: MRI detection of secondary damage after stroke: chronic iron accumulation in the thalamus of the rat brain. Stroke 2008;39:1541-1547.
20.
Ogawa T, Yoshida Y, Okudera T, Noguchi K, Kado H, Uemura K: Secondary thalamic degeneration after cerebral infarction in the middle cerebral artery distribution: evaluation with MR imaging. Radiology 1997;204:255-262.
21.
Sørensen JC, Dalmau I, Zimmer J, Finsen B: Microglial reactions to retrograde degeneration of tracer-identified thalamic neurons after frontal sensorimotor cortex lesions in adult rats. Exp Brain Res 1996;112:203-212.
22.
Tokuno T, Kataoka K, Asai T, Chichibu S, Kuroda R, Ioku M, Yamada K, Hayakawa T: Functional changes in thalamic relay neurons after focal cerebral infarct: a study of unit recordings from VPL neurons after MCA occlusion in rats. J Cereb Blood Flow Metab 1992;12:954-961.
23.
Nakane M, Tamura A, Sasaki Y, Teraoka A: MRI of secondary changes in the thalamus following a cerebral infarct. Neuroradiology 2002;44:915-920.
24.
Li C, Ling X, Liu S, Xu A, Zhang Y, Xing S, Pei Z, Zeng J: Early detection of secondary damage in ipsilateral thalamus after acute infarction at unilateral corona radiata by diffusion tensor imaging and magnetic resonance spectroscopy. BMC Neurol 2011;11:49.
25.
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke 1993;24:35-41.
26.
Fujie W, Kirino T, Tomukai N, Iwasawa T, Tamura A: Progressive shrinkage of the thalamus following middle cerebral artery occlusion in rats. Stroke 1990;21:1485-1488.
27.
Moos T, Rosengren Nielsen T, Skjorringe T, Morgan EH: Iron trafficking inside the brain. J Neurochem 2007;103:1730-1740.
28.
Dietrich RB, Bradley WG: Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children. Radiology 1988;168:203-206.
29.
Palmer C, Menzies SL, Roberts RL, Pavlick G, Connor JR: Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat. J Neurosci Res 1999;56:60-71.
30.
Kaplan J, Jordan I, Sturrock A: Regulation of the transferrin-independent iron transport system in cultured cells. J Biol Chem 1991;266:2997-3004.
31.
Schmahmann JD: Vascular syndromes of the thalamus. Stroke 2003;34:2264-2278.
32.
Haacke EM, Cheng NY, House MJ, Liu Q, Neelavalli J, Ogg RJ, Khan A, Ayaz M, Kirsch W, Obenaus A: Imaging iron stores in the brain using magnetic resonance imaging. Magn Reson Imaging 2005;23:1-25.
33.
Bagnato F, Hametner S, Yao B, van Gelderen P, Merkle H, Cantor FK, Lassmann H, Duyn JH: Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 tesla. Brain 2011;134:3602-3615.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.