The concept of a mismatch between the lesion volume in diffusion- and perfusion-weighted magnetic resonance imaging (MRI) indicating ‘tissue at risk of infarction’ is based on the assumption that tissue with diffusion slowing in diffusion-weighted MRI (DWI) or decreased values of the apparent diffusion coefficient represents irreversibly damaged tissue. Recent experimental as well as clinical studies, however, have shown that tissue with diffusion slowing may well normalize if the hypoperfusion is moderate or transient. We will interpret these findings in the light of experimental data and suggest a way for the interpretation of different time courses of lesion development in DWI within a clinical MRI protocol. MR stroke imaging delivers important information in acute stroke, particularly in defining the ‘tissue at risk of infarction’.

1.
Albers GW: Expanding the window for thrombolytic therapy in acute stroke: The potential role of acute MRI for patient selection. Stroke 1999;30:2230–2237.
2.
Neumann-Haefelin T, Moseley ME, Albers BW: New magnetic resonance imaging methods for cerebrovascular disease: Emerging clinical applications. Ann Neurol 2000;47:559–570.
3.
Schellinger PD, Jansen O, Fiebach JB, Pohlers O, Ryssel H, Helland S, Steiner T, Hacke W, Sartor K: Feasibility and practicality of MR imaging of stroke in the management of hyperacute cerebral ischemia. AJNR Am J Neuroradiol 2000;21:1184–1189.
4.
Lansberg MG, Albers GW, Beaulieu C, Marks MP: Comparison of diffusion-weighted MRI and CT in acute stroke. Neurology 2000;54:1557–1561.
5.
Fiebach J, Jansen O, Schellinger P, Knauth M, Hartmann M, Heiland S, Ryssel H, Pohlers O, Hacke W, Sartor K: Comparison of CT with diffusion-weighted MRI in patients with hyperacute stroke. Neuroradiology 2001;43:628–632.
6.
Hoehn-Berlage M: Diffusion-weighted NMR imaging: Application to experimental focal cerebral ischemia. NMR 1995;8:345–358.
7.
Hoehn M, Nicolay K, Franke C, van der Sanden B: Application of magnetic resonance to animal models of cerebral ischemia. J Magn Reson Imaging 2001;14:491–509.
8.
Karonen JO, Vanninen RL, Liu Y, Ostergaard L, Kuikka JT, Nuutinen J, Vanninen EJ, Partanen PL, Vainio PA, Korhonen K, Perkio J, Roivainen R, Sivenius J, Aronen HJ: Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke: Ischemic penumbra predicts infarct growth. Stroke 19999;30:1583–1590.
9.
Miyabe M, Mori S, van Zijl P, Kirsch J, Eleff S, Koehler R, Traystman R: Correlation of the average water diffusion constant with cerebral blood flow and ischemic damage after transient middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 1996;16:881–891.
10.
Hasegawa Y, Fisher M, Latour LL, Dardzinski BJ, Sotak CH: MRI diffusion mapping of reversible and irreversible ischemic injury in focal brain ischemia. Neurology 1994;44:1484–1490.
11.
Neumann-Haefelin T, Kastrup A, de Crespigny A, Yenari MA, Ringer T, Sun GH, Moseley ME: Serial MRI after transient focal cerebral ischemia in rats: Dynamics of tissue injury, blood-brain barrier damage, and edema formation. Stroke 2000;31:1965–1973.
12.
Li F, Liu KF, Silva MD, Omae T, Sotak CH, Fenstermacher JD, Fisher M, Hsu CY, Lin W: Transient and permanent resolution of ischemic lesions on diffusion-weighted imaging after brief periods of focal ischemia in rats: Correlation with histopathology. Stroke 2000;31:946–954.
13.
Kidwell C, Saver J, Mattiello J, Starkman S, Vinuela F, Duckwiler G, Gobin Y, Jahan R, Vespa P, Kalafut M, Alger J: Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol 2000;47:462–469.
14.
Kidwell CS, Alger JR, Di Salle F, Starkman S, Villablanca P, Bentson J, Saver JL: Diffusion MRI in patients with transient ischemic attacks. Stroke 1999;30:1174–1180.
15.
Neumann-Haefelin T, Wittsack H, Wenserski F, Li Tu, Moseley M, Siebler M, Freund H: Diffusion- and perfusion-weighted MRI in a patient with a prolonged reversible ischaemic neurological deficit. Neuroradiology 2000;42:444–447.
16.
Doege C, Kerskens C, Romero B, Brunecker P, Junge-Hülsing J, Müller B, Villringer A: MRI of small human stroke shows reversible diffusion changes in subcortical gray matter. Neuroreport 2000;11:2021–2024.
17.
Fiehler J, Foth M, Kucinski T, Schleper B, Knab R, Foth M, von Bezold M, Weiller C, Zeumer H, Röther J: Severe ADC decreases do not predict irreversible tissue damage. Stroke 2002;33/1:79–86.
18.
Ay H, Buonanno FS, Rordorf G, Schaefer PW, Schwamm LH, Wu O, Gonzalez RG, Yamada K, Sorensen GA, Koroshetz WJ: Normal diffusion-weighted MRI during stroke-life deficits. Neurology 1999;52:1784–1792.
19.
Wang P, Barker P, Wityk R, Ulug A, van Zijl P, Beauchamp N: Diffusion-negative stroke: A report of two cases. AJNR Am J Neuroradiol 1999;20:1179–1184.
20.
Lefkowitz D, LaBenz M, Nudo S, Steg R, Beroni J: Hyperacute ischemic stroke missed by diffusion-weighted imaging. AJNR Am J Neuroradiol 2000;20:1871–1875.
21.
Oppenheim C, Stanescu R, Dormont D, Crozier S, Marro B, Samson Y, Rancurel G, Marsault C: False-negative diffusion-weighted MR findings in acute ischemic stroke. AJNR Am J Neuroradiol 2000:21:1434–1440.
22.
Le Bihan D, Breton E, Lallemand D, Grenier P, Cabanis E, Laval-Jeantet M: MR imaging of intravoxel incoherent motions: Application to diffusion and perfusion in neurologic disorders. Radiology 1986;161:401–407.
23.
Basser PJ: Inferring microstructural features and the physiological state of tissues from diffusion weighted images. NMR Biomed 1995;8:333–344.
24.
Pierpaoli C, Jezzard P, Basser PJ, Barnètt A, Di Chiro G: Diffusion tensor MR imaging of the human brain. Radiology 1996;201:637–648.
25.
Norris D, Niendorf T: Interpretation of DW-NMR data: Dependence on experimental conditions. NMR Biomed 1995;8:280–288.
26.
Schuler FJ, Hossmann K-A: Experimental brain infarcts in cats. II. Ischemic brain edema. Stroke 1980;11:593–601.
27.
Unger E, Littlefield J, Gado M: Water content and water structure in CT and MR signal changes: Possible influence in detection of early stroke. AJNR Am J Neuroradiol 1988;9:687–691.
28.
Marks MP, Tong DC, Beaulieu C, Albers GW, de Crespigny A, Moseley ME: Evaluation of early reperfusion and i.v. tPA therapy using diffusion- and perfusion-weighted MRI. Neurology 1999;52:1792–1798.
29.
Schlaug G, Siewert B, Benfield A, Edelman RR, Warach S: Time course of the apparent diffusion coefficient (ADC) abnormality in human stroke. Neurology 1997;49:113–1119.
30.
Hossmann KA: Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994;36:557–565.
31.
Heiss W: Ischemic penumbra: Evidence from functional imaging in man. J Cereb Blood Flow Metab 2000;20:1276–1293.
32.
Röther J, de Crespigny AJ, D’Arceuil H, Moseley ME: MR detection of cortical spreading depression immediately after focal ischemia in the rat. J Cereb Blood Flow Metab 1996;16:214–220.
33.
de Crespigny AJ, Röther J, Beaulieu C, Moseley ME, Hoehn M: Rapid monitoring of diffusion, DC potential, and blood oxygenation changes during global ischemia. Effects of hypoglycemia, hyperglycemia, and TTX. Stroke 1999;30:2212–2222.
34.
Hossmann K-A, Fischer M, Bockhorst K, Hoehn-Berlage M: NMR imaging of the apparent diffusion coefficient (ADC) for the evaluation of metabolic suppression and recovery after prolonged cerebral ischemia. J Cereb Blood Flow Metab 1994;14:723–731.
35.
Hasegawa Y, Latour L, Formato J, Sotak C, Fisher M: Spreading waves of reduced diffusion coefficient of water in normal and ischemic rat brain. J Cereb Blood Flow Metab 1995;15:179–187.
36.
Röther j, de Crespigny AJ, D’Arceuil H, Iwai K, Moseley ME: Recovery of apparent diffusion coefficient after ischemia-induced spreading depression relates to cerebral perfusion gradient. Stroke 1996;27:980–987.
37.
Gyngell M, Back T, Hoehn-Berlage M, Kohno K, Hossmann K-A: Transient cell depolarization after permanent middle cerebral artery occlusion: An observation by diffusion-weighted MRI and localized 1H-MRS. Magn Reson Med 1994;31:337–341.
38.
Busch E, Hoehn-Berlage M, Eis M, Gyngell M, Hossmann K-A: Simultaneous recording of EEG, DC potential and difusion-weighted NMR imaging during potassium induced cortical spreading depression in rats. NMR Biomed 1995;8:59–64.
39.
Hasegawa A, Formato JE, Latour LL, Gutierrez JA, Liu KF, Garcia J, Sotak C, Fisher M. Severe transient hypoglycemia causes reversible change in the apparent diffusion coefficient of water. Stroke 1996;27:1649–1656.
40.
Prichard JW, Zhong J, Petroff OA, Gore JC: Diffusion-weighted NMR imaging changes caused by electrical activation of the brain. NMR Biomed 1995;8:359–364.
41.
Zhong J, Petroff OA, Pleban LA, Gore JC, Prichard JW: Reversible, reproducible reduction of brain water apparent diffusion coefficient by cortical electroshocks. Magn Reson Med 1997;37:1–6.
42.
Lansberg MG, O’Brien MW, Norbash AM, Moseley ME, Morrell M, Albers GW: MRI abnormalities associated with partial status epilepticus. Neurology 1999;62:1021–1027.
43.
Gass A, Hirsch J, Fritzinger M, Hennerici M, Gaa J, Pohlmann-Eden B: Multiparametric postictal and ictal MRI detects reversible tissue changes in patients with complex partial seizures. Epilepsia 2000;41(suppl 7):67–68.
44.
Darquie A, Poline JB, Poupon C, Saint-Jalmes H, Le Bihan D: Transient decrease in water diffusion observed in human occipital cortex during visual stimulation. Proc Natl Acad Sci USA 2001;98:9391–9395.
45.
Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H. Kucharczyk J, Wendland MF, Weinstein PR: Early detection of regional cerebral ischemia in cats: Comparison of diffusion- and T2-weighted MRI for the early detection of cerebral ischemia and reperfusion in rats. Magn Reson Med 1990;14:330–346.
46.
Benveniste H, Hedlund LW, Johnson GA: Mechanism of detection of acute cerebral ischemia in rats by diffusion-weighted magnetic resonance microscopy. Stroke 1992;23:746–754.
47.
Hossmann K-A, Fischer M, Bockhorst K, Hoehn-Berlage M: NMR imaging of the apparent diffusion coefficient (ADC) for the evaluation of metabolic suppression and recovery after prolonged cerebral ischemia. J Cereb Blood Flow Metab 1994;14:723–731.
48.
Kuroiwa T, Nagaoka T, Ueki M, Yamada I, Miyasaka N, Akimoto H: Different apparent diffusion coefficient: Water content correlations of gray and white matter during early ischemia. Stroke 1998;29:859–865.
49.
Anderson A, Xie J, Pizzonia J, Bronen R, Spencer D, Gore J: Effects of cell volume fraction changes on apparent diffusion in human cells. Magn Reson Imaging 2000;19:689–695.
50.
Mintorovitch J, Moseley ME, Chileuitt L, Shimizu H, Cohen Y, Weinstein PR: Comparison of diffusion- and T2-weighted MRI for the early detection of cerebral ischemia and reperfusion in rats. Magn Reson Med 1991;18:39–50.
51.
Le Bihan D, Breton E, Lallemand D, Aubin ML, Vignaud J, Laval-Jeantet M: Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology 1988;168:497–505.
52.
Bizzi A, Righini A, Turner R, LeBihan D, DesPres D, Di Chiro G, Alger JR: MR of diffusion slowing in global cerebral ischemia. AJNR Am J Neuroradiol 1993;14:1347–1354.
53.
Szafer A, Zhong J, Anderson AW, Gore JC: Diffusion-weighted imaging in tissues: Theoretical models. NMR Biomed 1995;8:289–296.
54.
van der Toorn A, Sykova E, Dijkhuizen RM, Vorisek I, Vargova L, Skobisova E, van Lookeren Campagne M, Reese T, Nicolay K: Dynamik changes in water ADC, energy metabolism, extracellular space volume, and tortuosity in neonatal rat brain during global ischemia. Magn Reson Med 1996;36:52–60.
55.
Helpern J, Ordidge R, Kinght R: The effect of cell membrane water permeability on the apparent diffusion coefficient of water. Society of Magnetic Resonance in Medicine, 11th Annual Meeting. Berlin, Germany, vol 1, p 1201.
56.
Wick M, Nagatorno Y, Prielmeier F, Frahm J: Alteration of intracellular metabolite diffusion in rat brain in vivo during ischemia and reperfusion. Stroke 1995;26:1930–1934.
57.
O’Shea J, Williams S, van Bruggen N, Gardner-Medwin A: Apparent diffusion coefficient and MR relaxation during osmotic manipulation in isolated turtle cerebellum. Magn Reson Med 2000;44:427–432.
58.
Hoehn-Berlage M, Norris D, Kohno K, Mies G, Leibfritz D, Hossmann K: 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;15:1002–1011.
59.
Kohno K, Hoehn-Berlage M, Mies G, Back T, Hossmann K-A: Relationship between diffusion-weighted magnetic resonance images, cerebral blood flow, and energy state in experimental brain infarction. Magn Reson Med 1995;13:65–71.
60.
Matsuoka Y, Hossmann KA: Cortical impedance and extracellular volume changes following middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 1982;2:466–474.
61.
Hossmann KA, Mies G, Paschen W, Csiba L, Bodsch W, Rapin JR, Le Poncin-Lafitte M, Takahashi K: Multiparametric imaging of blood flow and metabolism after middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 1985;5:97–107.
62.
Gass A, Szabo K, Behrens S, Hirsch J, Hennerici M: Subgroup analysis of patients with severe acute neurological syndromes without diffusion weighted MRI abnormalities. Stroke 2001;32:318.
63.
Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR: Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 1995;37:231–241.
64.
Marks MP, de Crespigny A, Lentz D, Enzmann DR, Albers GW, Moseley ME: Acute and chronic stroke: Navigated spin-echo diffusion-weighted MR imaging. Radiology 1996;199:403–408.
65.
Gass A, Behrens S, Gaa J, Schwartz A, Georgi M, Hennerici M: Intralesional heterogeneity of the time course of the apparent diffusion coefficient in large territorial infarction. Stroke 1999;30:260.
66.
Lutsep HL, Albers GW, DeCrespigny A, Kamat GN, Marks MP, Moseley ME: Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke. Ann Neurol 1997;41:574–580.
67.
Abe K, Aoki M, Kawagoe J, Yoshida T, Hattori A, Kogure K, Itoyama Y: Ischemic delayed neuronal death. A mitochondrial hypothesis. Stroke 1995;26:1478–1489.
68.
Miyasaka N, Kuroiwa T, Zhao FY, Nagaoka T, Akimoto H, Yamada I, Kubota T, Aso T: Cerebral ischemic hypoxia: Discrepancy between apparent diffusion coefficients and histologic changes in rats. Radiology 2000;215:199–204.
69.
Tong D, Adami A, Moseley M, Marks M: Relationship between apparent diffusion coefficient and subsequent hemorrhagic transformation following acute ischemic stroke. Stroke 2000;31:2378–2384.
70.
Dijkhuizen RM, Knollema S, van der Worp HB, Ter Horst GJ, De Wildt DJ, Berkelbach van der Sprenkel JW, Tulleken KA, Nicolay K: Dynamics of cerebral tissue injury and perfusion after temporary hypoxia-ischemia in the rat: Evidence for region-specific sensitivity and delayed damage. Stroke 1998;29:695–704.
71.
Reith W, Hasegawa Y, Latour LL, Dardzinski BJ, Sotak CH, Fisher M: Multislice diffusion mapping for 3-D evolution of cerebral ischemia in a rat stroke model. Neurology 1995;45:172–177.
72.
Fiehler J, Knab R, Reichenbach JR, Fitzek C, Weiller C, Röther J: Apparent diffusion coefficient decreases and magnetic resonance imaging perfusion parameters are associated in ischemic tissue of acute stroke patients. J Cereb Blood Flow Metab 2001;21:577–584.
73.
Mancuso A, Karibe H, Rooney WD, Zarow GJ, Graham SH, Weiner MW, Weinstein PR: Correlation of early reduction in the apparent diffusion coefficient of water with blood flow reduction during middle cerebral artery occlusion in rats. Magn Reson Med 1995;34:368–377.
74.
Schlaug G, Benfield A, Baird A, Siewert B, Lovblad K, Parker R, Edelman R, Warach S: The ischemic penumbra: Operationally defined by diffusion and perfusion MRI. Neurology 1999;53:1528–1537.
75.
Li F, Silva MD, Liu KF, Helmer KG, Omae T, Fenstermacher JD, Sotak CH, Fisher M: Secondary decline in apparent diffusion coefficient and neurological outcomes after a short period of focal brain ischemia in rats. Ann Neurol 2000;48:236–244.
76.
Davis D, Ulatowski J, Eleff S, Izuta M, Mori S, Shungu D, van Zijl P: Rapid monitoring of changes in water diffusion coefficients during reversible ischemia in cat and rat brain. Magn Reson Med 1994;31:454–460.
77.
Olah L, Wecker S, Hoehn M: Secondary deterioration of ADC after one hour transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2000;20:1474–1482.
78.
Olah L, Wecker S, Hoehn M: Relation of ADC changes and metabolic disturbances after 1 hour focal cerebral ischemia and at different reperfusion phases in rats. J Cereb Blood Flow Metab 2001;21:430–439.
79.
Vogt C, Vogt O: Erkrankungen der Grosshirnrinde im Lichte der Topistik. J Psychol Neurol 1922;28:9–68.
80.
Ginsberg MD, Medoff R, Reivich M: Heterogeneities of regional cerebral blood flow during hypoxia-ischemia in the rat. Stroke 1976;7/2:132–134.
81.
Pulsinelli W, Levy D, Duffy T: Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia. Ann Neurol 1982;11:499–509.
82.
Memezawa H, Smith ML, Siesjo BK: Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 1992;23:552–559.
83.
Hoehn-Berlage M, Eis M, Schmitz B: Regional and directional anisotropy of apparent diffusion coefficient in rat brain. NMR Biomed 1999;12:45–50.
84.
Knight RA, Dereski MO, Helpern JA, Ordidge RJ, Chopp M: Magnetic resonance imaging assessment of evolving focal cerebral ischemia. Comparison with histopathology in rats. Stroke 1994;25:1252–1262.
85.
Jiang Q, Zhang ZG, Chopp M, Helpern JA, Ordidge RJ, Garcia JH, Marchese BA, Quing ZX, Knight RA: Temporal evolution and spatial distribution of the diffusion constant of water in rat brain after transient middle cerebral artery occlusion. J Neurol Sci 1993;120:123–130.
86.
Mancuso A, Nimura T, Weinstein PR: Prediction of delayed ischemic injury with diffusion-weighted MRI following temporary middle cerebral artery occlusion in rats. Brain Res 1997;760:42–51.
87.
DeLaPaz RL, Shibata D, Steinberg GK, Zarnegar R, George C: Acute cerebral ischemia in rabbits: Correlation between MR and histopathology. AJNR Am J Neuroradiol 1991;12:89–95.
88.
Li F, Han SS, Tatlisumak T, Liu KF, Garcia JH, Sotak CH, Fisher M: Reversal of acute apparent diffusion coefficient abnormalities and delayed neuronal death following transient focal cerebral ischemia in rats. Ann Neurol 1999;46:333–342.
89.
Pillekamp F, Grüne M, Brinker G, Franke C, Uhlenküken U, Hoehn M, Hossmann K-A: Magnetic resonance prediction of outcome after thrombolytic treatment. Magn Reson Imaging 2001;19:143–152.
90.
van Dorsten F, Olah L, Schwindt W, Grüne M, Uhlenküken U, Pillekamp F, Hossmann K, Hoehn M: Dynamic changes of ADC, perfusion, and NMR relaxation parameters in transient focal ischemia of rat brain. Magn Reson Med 2002;47/1:97–104.
91.
Lutsep HL, Nesbit GM, Berger RM, Coshow WR: Does reversal of ischemia on diffusion-weighted imaging reflect higher apparent diffusion coefficient values? J Neuroimaging 2001;11:313–316.
92.
Röther J, Schleper B, Fiehler J, Kucinski T, Knab R, Bohuslavizki K, Weiller C, Zeumer H: The fate of saved ‘tissue at risk of infarction’. International Society of Magnetic Resonance in Medicine, 9th Scientific Meeting, Denver, Colo., ISMRM, 2001, 1428.
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.