Skip to main content

Advertisement

Log in

Defining an Acidosis-Based Ischemic Penumbra from pH-Weighted MRI

  • Review Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

It has been proposed that the spatial mismatch between deficits on perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in MRI can be used to decide regarding thrombolytic treatment in acute stroke. However, uncertainty remains about the meaning and reversibility of the perfusion deficit and even part of the diffusion deficit. Thus, there remains a need for continued development of imaging technology that can better define a potentially salvageable ischemic area at risk of infarction. Amide proton transfer imaging is a novel MRI method that can map tissue pH changes, thus providing the potential to separate the PWI/DWI mismatch into an acidosis-based penumbra and a zone of benign oligemia. In this totally noninvasive method, the pH dependence of the chemical exchange between amide protons in endogenous proteins and peptides and water protons is exploited. Early results in animal models of ischemia show promise to derive an acidosis penumbra. Possible translation to the clinic and hurdles standing in the way of achieving this are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. World Health Organization. Available at http://gamapserver.who.int/gho/interactive_charts/mbd/cod_2008/graph.html

  2. Donnan GA, Baron JC, Ma H, Davis SM. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol. 2009;8(3):261–9.

    Article  PubMed  CAS  Google Scholar 

  3. Wintermark M, Albers GW, Alexandrov AV, Alger JR, Bammer R, Baron JC, et al. Acute stroke imaging research roadmap. Stroke. 2008;39(5):1621–8.

    Article  PubMed  Google Scholar 

  4. Astrup J. Thresholds of cerebral ischemia. In: Schmiedek P, editor. Microsurgery for stroke. Berlin: Springer; 1976. p. 16–21.

    Google Scholar 

  5. Baron JC, Marchal G. Ischemic core and penumbra in human stroke. Stroke. 1999;30(5):1150–3.

    Article  PubMed  CAS  Google Scholar 

  6. Heiss WD. The concept of the penumbra: can it be translated to stroke management? Int J Stroke. 2010;5(4):290–5.

    Article  PubMed  Google Scholar 

  7. Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol. 1994;36(4):557–65.

    Article  PubMed  CAS  Google Scholar 

  8. Moseley ME, Sevick R, Wendland MF, White DL, Mintorovitch J, Asgari HS, et al. Ultrafast magnetic resonance imaging: diffusion and perfusion. Can Assoc Radiol J. 1991;42(1):31–8.

    PubMed  CAS  Google Scholar 

  9. Moseley ME, Mintorovitch J, Cohen Y, Asgari HS, Derugin N, Norman D, et al. Early detection of ischemic injury: comparison of spectroscopy, diffusion-, T2-, and magnetic susceptibility-weighted MRI in cats. Acta Neurochir Suppl Wien. 1990;51:207–9.

    PubMed  CAS  Google Scholar 

  10. Neumann-Haefelin T, Wittsack HJ, Wenserski F, Siebler M, Seitz RJ, Modder U, et al. Diffusion-and perfusion-weighted MRI—the DWI/PWI mismatch region in acute stroke. Stroke. 1999;30(8):1591–7.

    Article  PubMed  CAS  Google Scholar 

  11. Schaefer PW, Grant PE, Gonzalez RG. Diffusion-weighted MR imaging of the brain. Radiology. 2000;217(2):331–45.

    PubMed  CAS  Google Scholar 

  12. Schellinger PD, Jansen O, Fiebach JB, Heiland S, Steiner T, Schwab SF, et al. Monitoring intravenous recombinant tissue plasminogen activator thrombolysis for acute ischemic stroke with diffusion and perfusion MRI. Stroke. 2000;31(6):1318–28.

    Article  PubMed  CAS  Google Scholar 

  13. Schlaug G, Benfield A, Baird AE, Siewert B, Lovblad KO, Parker RA, et al. The ischemic penumbra—operationally defined by diffusion and perfusion MRI. Neurology. 1999;53(7):1528–37.

    PubMed  CAS  Google Scholar 

  14. Wu O, Koroshetz WJ, Ostergaard L, Buonanno FS, Copen WA, Gonzalez RG, et al. Predicting tissue outcome in acute human cerebral ischemia using combined diffusion- and perfusion-weighted MR imaging. Stroke. 2001;32(4):933–42.

    Article  PubMed  CAS  Google Scholar 

  15. Albers GW, Thijs VN, Wechsle L, Kemp S, Schlaug G, Skalabrin E, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurology. 2006;60(5):508–17.

    Article  Google Scholar 

  16. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et al. Effects of alteplase beyond 3 h after stroke in the echoplanar imaging thrombolytic evaluation trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7(4):299–309.

    Article  PubMed  Google Scholar 

  17. Kidwell CS, Alger JR, Saver JL. Evolving paradigms in neuroimaging of the ischemic penumbra. Stroke. 2004;35(11 Suppl 1):2662–5.

    Article  PubMed  Google Scholar 

  18. Nicoli F, Lefur Y, Denis B, Ranjeva JP, Confort-Gouny S, Cozzone PJ. Metabolic counterpart of decreased apparent diffusion coefficient during hyperacute ischemic stroke: a brain proton magnetic resonance spectroscopic imaging study. Stroke. 2003;34(7):e82–7.

    Article  PubMed  CAS  Google Scholar 

  19. Butcher KS, Parsons M, MacGregor L, Barber PA, Chalk J, Bladin C, et al. Refining the perfusion–diffusion mismatch hypothesis. Stroke. 2005;36(6):1153–9.

    Article  PubMed  CAS  Google Scholar 

  20. Kakuda W, Lansberg MG, Thijs VN, Kemp SM, Bammer R, Wechsler LR, et al. Optimal definition for PWI/DWI mismatch in acute ischemic stroke patients. J Cereb Blood Flow Metab. 2008;28(5):887–91.

    Article  PubMed  Google Scholar 

  21. Toth G, Albers GW. Use of MRI to estimate the therapeutic window in acute stroke: Is perfusion-weighted imaging/diffusion-weighted imaging mismatch an EPITHET for salvageable ischemic brain tissue? Stroke. 2009;40(1):333–5.

    Article  PubMed  Google Scholar 

  22. Wu O, Ostergaard L, Koroshetz WJ, Schwamm LH, O'Donnell J, Schaefer PW, et al. Effects of tracer arrival time on flow estimates in MR perfusion-weighted imaging. Magn Reson Med. 2003;50(4):856–64.

    Article  PubMed  Google Scholar 

  23. Davis D, Ulatowski J, Eleff S, Izuta M, Mori S, Shungu D, et al. Rapid monitoring of changes in water diffusion coefficients during reversible ischemia in cat and rat brain. Magn Reson Med. 1994;31(4):454–60.

    Article  PubMed  CAS  Google Scholar 

  24. Minematsu K, Li L, Sotak CH, Davis MA, Fisher M. Reversible focal ischemic injury demonstrated by diffusion-weighted magnetic resonance imaging in rats. Stroke. 1992;23(9):1304–10. discussion 1310–1301.

    Article  PubMed  CAS  Google Scholar 

  25. Crockard HA, Gadian DG, Frackowiak RS, Proctor E, Allen K, Williams SR, et al. Acute cerebral ischaemia: concurrent changes in cerebral blood flow, energy metabolites, pH, and lactate measured with hydrogen clearance and 31P and 1H nuclear magnetic resonance spectroscopy. II. Changes during ischaemia. J Cereb Blood Flow Metab. 1987;7(4):394–402.

    Article  PubMed  CAS  Google Scholar 

  26. Zhou J, Payen JF, Wilson DA, Traystman RJ, van Zijl PC. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat Med. 2003;9(8):1085–90.

    Article  PubMed  CAS  Google Scholar 

  27. Englander SW, Downer NW, Teitelbaum H. Hydrogen exchange. Annu Rev Biochem. 1972;41:903–24.

    Article  PubMed  CAS  Google Scholar 

  28. Wuthrich K. NMR of proteins and nucleic acids. New York: Wiley; 1986.

    Google Scholar 

  29. Mori S, Eleff SM, Pilatus U, Mori N, van Zijl PCM. Proton NMR spectroscopy of solvent-saturable resonance: a new approach to study pH effects in situ. Magn Reson Med. 1998;40:36–42.

    Article  PubMed  CAS  Google Scholar 

  30. van Zijl PCM, Zhou J, Mori N, Payen J, Mori S. Mechanism of magnetization transfer during on-resonance water saturation. A new approach to detect mobile proteins, peptides, and lipids. Magn Reson Med. 2003;49:440–9.

    Article  PubMed  Google Scholar 

  31. Ward KM, Aletras AH, Balaban RS. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson. 2000;143:79–87.

    Article  PubMed  CAS  Google Scholar 

  32. Zhou J, van Zijl PC. Chemical exchange saturation transfer imaging and spectroscopy. Progr NMR Spectr. 2006;48:109–36.

    Article  CAS  Google Scholar 

  33. van Zijl PC, Yadav NN. Chemical exchange saturation transfer (CEST): what is in a name and what isn't? Magn Reson Med. 2011;65(4):927–48.

    Article  PubMed  Google Scholar 

  34. Balaban RS, Ceckler TL. Magnetization transfer contrast in magnetic resonance imaging. Magn Reson Q. 1992;8:116–37.

    PubMed  CAS  Google Scholar 

  35. Henkelman RM, Stanisz GJ, Graham SJ. Magnetization transfer in MRI: a review. NMR Biomed. 2001;14:57–64.

    Article  PubMed  CAS  Google Scholar 

  36. Zhou J, Lal B, Wilson DA, Laterra J, van Zijl PC. Amide proton transfer (APT) contrast for imaging of brain tumors. Magn Reson Med. 2003;50(6):1120–6.

    Article  PubMed  Google Scholar 

  37. Zhou J, Tryggestad E, Wen Z, Lal B, Zhou T, Grossman R, et al. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nat Med. 2011;17(1):130–4.

    Article  PubMed  CAS  Google Scholar 

  38. Jokivarsi KT, Grohn HI, Grohn OH, Kauppinen RA. Proton transfer ratio, lactate, and intracellular pH in acute cerebral ischemia. Magn Reson Med. 2007;57(4):647–53.

    Article  PubMed  CAS  Google Scholar 

  39. Jokivarsi KT, Hiltunen Y, Tuunanen PI, Kauppinen RA, Grohn OH. Correlating tissue outcome with quantitative multiparametric MRI of acute cerebral ischemia in rats. J Cereb Blood Flow Metab. 2010;30(2):415–27.

    Article  PubMed  Google Scholar 

  40. Sun PZ, Murata Y, Lu J, Wang X, Lo EH, Sorensen AG. Relaxation-compensated fast multislice amide proton transfer (APT) imaging of acute ischemic stroke. Magn Reson Med. 2008;59(5):1175–82.

    Article  PubMed  Google Scholar 

  41. Sun PZ, Zhou J, Sun W, Huang J, van Zijl PC. Detection of the ischemic penumbra using pH-weighted MRI. J Cereb Blood Flow Metab. 2007;27(6):1129–36.

    Article  PubMed  Google Scholar 

  42. Shen Q, Meng X, Fisher M, Sotak CH, Duong TQ. Pixel-by-pixel spatiotemporal progression of focal ischemia derived using quantitative perfusion and diffusion imaging. J Cereb Blood Flow Metab. 2003;23:1479–88.

    Article  PubMed  Google Scholar 

  43. Katsura K, Asplund B, Ekholm A, Siesjo BK. Extra- and Intracellular pH in the brain during ischaemia, related to tissue lactate content in normo- and hypercapnic rats. Eur J Neurosci. 1992;4(2):166–76.

    Article  PubMed  Google Scholar 

  44. Allen K, Busza AL, Crockard HA, Frackowiak RS, Gadian DG, Proctor E, et al. Acute cerebral ischaemia: concurrent changes in cerebral blood flow, energy metabolites, pH, and lactate measured with hydrogen clearance and 31P and 1H nuclear magnetic resonance spectroscopy. III. Changes following ischaemia. J Cereb Blood Flow Metab. 1988;8(6):816–21.

    Article  PubMed  CAS  Google Scholar 

  45. Jones CK, Schlosser MJ, van Zijl PC, Pomper MG, Golay X, Zhou J. Amide proton transfer imaging of human brain tumors at 3 T. Magn Reson Med. 2006;56(3):585–92.

    Article  PubMed  Google Scholar 

  46. Schmitt B, Zaiß M, Zhou J, Bachert P. Optimization of pulse train presaturation for CEST imaging in clinical scanners. Magn Reson Med. 2011;65:1620–9.

    Article  PubMed  Google Scholar 

  47. Sun PZ, Wang E, Cheung JS, Zhang X, Benner T, Sorensen AG. Simulation and optimization of pulsed radio frequency irradiation scheme for chemical exchange saturation transfer (CEST) MRI-demonstration of pH-weighted pulsed-amide proton CEST MRI in an animal model of acute cerebral ischemia. Magn Reson Med. 2011;66(4):1042–8. doi:10.1002/mrm.22894.

    Article  PubMed  Google Scholar 

  48. Zhao X, Wen Z, Huang F, Lu S, Wang X, Hu S, et al. Saturation power dependence of amide proton transfer image contrasts in human brain tumors and strokes at 3 T. Magn Reson Med. 2011;66(4):1033–41. doi:10.1002/mrm.22891.

    Article  PubMed  Google Scholar 

  49. Zhou J. Amide proton transfer imaging of the human brain. Methods Mol Biol. 2011;711:227–37.

    Article  PubMed  CAS  Google Scholar 

  50. Wen Z, Hu S, Huang F, Wang X, Guo L, Quan X, et al. MR imaging of high-grade brain tumors using endogenous protein and peptide-based contrast. NeuroImage. 2010;51(2):616–22.

    Article  PubMed  Google Scholar 

  51. Zhou J, Blakeley JO, Hua J, Kim M, Laterra J, Pomper MG, et al. Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging. Magn Reson Med. 2008;60(4):842–9.

    Article  PubMed  Google Scholar 

  52. Jia GA, Abaza R, Williams JD, Zynger DL, Zhou JY, Shah ZK, et al. Amide proton transfer MR imaging of prostate cancer: a preliminary study. J Magn Reson Imaging. 2011;33(3):647–54.

    Article  PubMed  Google Scholar 

  53. Kim M, Gillen J, Landman BA, Zhou J, van Zijl PC. Water saturation shift referencing (WASSR) for chemical exchange saturation transfer (CEST) experiments. Magn Reson Med. 2009;61(6):1441–50.

    Article  PubMed  Google Scholar 

  54. Sun PZ, Farrar CT, Sorensen AG. Correction for artifacts induced by B(0) and B(1) field inhomogeneities in pH-sensitive chemical exchange saturation transfer (CEST) imaging. Magn Reson Med. 2007;58(6):1207–15.

    Article  PubMed  Google Scholar 

  55. Dixon WT, Hancu I, Ratnakar SJ, Sherry AD, Lenkinski RE, Alsop DC. A multislice gradient echo pulse sequence for CEST imaging. Magn Reson Med. 2010;63(1):253–6.

    PubMed  Google Scholar 

  56. Sun PZ, Cheung JS, Wang E, Benner T, Sorensen AG. Fast multislice pH-weighted chemical exchange saturation transfer (CEST) MRI with unevenly segmented RF irradiation. Magn Reson Med. 2011;65(2):588–94.

    Article  PubMed  Google Scholar 

  57. Zhu H, Jones CK, van Zijl PC, Barker PB, Zhou J. Fast 3D chemical exchange saturation transfer (CEST) imaging of the human brain. Magn Reson Med. 2010;64(3):638–44.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Dr. Ona Wu (MGH) for suggestions with the manuscript. This study was supported in part by grants from NIH (EB009112, EB009731, EB015032, and RR015241).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jinyuan Zhou or Peter C. M. van Zijl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, J., van Zijl, P.C.M. Defining an Acidosis-Based Ischemic Penumbra from pH-Weighted MRI. Transl. Stroke Res. 3, 76–83 (2012). https://doi.org/10.1007/s12975-011-0110-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-011-0110-4

Keywords

Navigation