Advertisement

Amide proton transfer–weighted MRI can detect tissue acidosis and monitor recovery in a transient middle cerebral artery occlusion model compared with a permanent occlusion model in rats

  • Ji Eun Park
  • Seung Chai Jung
  • Ho Sung KimEmail author
  • Ji-Yeon Suh
  • Jin Hee Baek
  • Chul-Woong Woo
  • Bumwoo Park
  • Dong-Cheol Woo
Neuro
  • 33 Downloads

Abstract

Objectives

To assess whether increases in amide proton transfer (APT)–weighted signal reflect the effects of tissue recovery from acidosis using transient rat middle cerebral artery occlusion (MCAO) models, compared to permanent occlusion models.

Materials and methods

Twenty-four rats with MCAO (17 transient and seven permanent occlusions) were prepared. APT-weighted signal (APTw), apparent diffusion coefficient (ADC), cerebral blood flow (CBF), and MR spectroscopy were evaluated at three stages in each group (occlusion, reperfusion/1 h post-occlusion, and 3 h post-reperfusion/4 h post-occlusion). Deficit areas showing 30% reduction to the contralateral side were measured. Temporal changes were compared with repeated measures of analysis of variance. Relationship between APTw and lactate concentration was calculated.

Results

Both APTw and CBF values increased and APTw deficit area reduced at reperfusion (largest p = .002) in transient occlusion models, but this was not demonstrated in permanent occlusion. No significant temporal change was demonstrated with ADC at reperfusion. APTw deficit area was between ADC and CBF deficit areas in transient occlusion model. APTw correlated with lactate concentration at occlusion (r = − 0.49, p = .04) and reperfusion (r = − 0.32, p = .02).

Conclusions

APTw values increased after reperfusion and correlated with lactate content, which suggests that APT-weighted MRI could become a useful imaging technique to reflect tissue acidosis and its reversal.

Key Points

APT-weighted signal increases in the tissue reperfusion, while remains stable in the permanent occlusion.

• APTw deficit area was between ADC and CBF deficit areas in transient occlusion model, possibly demonstrating metabolic penumbra.

• APTw correlated with lactate concentration during ischemia and reperfusion, indicating tissue acidosis.

Keywords

Acidosis Reperfusion Amides Magnetic resonance imaging 

Abbreviations

ADC

Apparent diffusion coefficient

APTw

Amide proton transfer–weighted signal

CBF

Cerebral blood flow

MCAO

Middle cerebral artery occlusion

Notes

Funding

This study was supported by a grant (2016-690) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

Compliance with ethical standards

Guarantor

The scientific guarantor of this publication is Dong Cheol Woo.

Conflict of interest

The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.

Statistics and biometry

We thank Seon Ok Kim for his expertise in statistical analysis.

Informed consent

Approval from the institutional animal care committee was obtained.

Ethical approval

This study was approved by the Institutional Animal Care and Use Committee of Asan Medical Center.

Methodology

• retrospective

• cross-sectional

• performed at one institution

Supplementary material

330_2018_5964_MOESM1_ESM.docx (19 kb)
ESM 1 (DOCX 19 kb)

References

  1. 1.
    Chesler M (2003) Regulation and modulation of pH in the brain. Physiol Rev 83:1183–1221CrossRefGoogle Scholar
  2. 2.
    Zhou J, Wilson DA, Sun PZ, Klaus JA, Van Zijl PC (2004) Quantitative description of proton exchange processes between water and endogenous and exogenous agents for WEX, CEST, and APT experiments. Magn Reson Med 51:945–952CrossRefGoogle Scholar
  3. 3.
    Zhou JY, Payen JF, Wilson DA, Traystman RJ, van Zijl PC (2003) Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat Med 9:1085–1090CrossRefGoogle Scholar
  4. 4.
    Sun PZ, Zhou J, Sun W, Huang J, van Zijl PC (2007) Detection of the ischemic penumbra using pH-weighted MRI. J Cereb Blood Flow Metab 27:1129–1136CrossRefGoogle Scholar
  5. 5.
    Zheng Y, Wang XM (2017) Measurement of lactate content and amide proton transfer values in the basal ganglia of a neonatal piglet hypoxic-ischemic brain injury model using MRI. AJNR Am J Neuroradiol 38:827–834CrossRefGoogle Scholar
  6. 6.
    Song G, Li C, Luo X et al (2017) Evolution of cerebral ischemia assessed by amide proton transfer-weighted MRI. Front Neurol 8:67PubMedPubMedCentralGoogle Scholar
  7. 7.
    Zhou J, van Zijl PC (2011) Defining an acidosis-based ischemic penumbra from pH-weighted MRI. Transl Stroke Res 3:76–83CrossRefGoogle Scholar
  8. 8.
    Heo HY, Zhang Y, Burton TM et al (2017) Improving the detection sensitivity of pH-weighted amide proton transfer MRI in acute stroke patients using extrapolated semisolid magnetization transfer reference signals. Magn Reson Med 78:871–880CrossRefGoogle Scholar
  9. 9.
    Zong X, Wang P, Kim SG, Jin T (2014) Sensitivity and source of amine-proton exchange and amide-proton transfer magnetic resonance imaging in cerebral ischemia. Magn Reson Med 71:118–132CrossRefGoogle Scholar
  10. 10.
    Sun PZ, Murata Y, Lu J, Wang X, Lo EH, Sorensen AG (2008) Relaxation-compensated fast multislice amide proton transfer (APT) imaging of acute ischemic stroke. Magn Reson Med 59:1175–1182CrossRefGoogle Scholar
  11. 11.
    Sun PZ, Benner T, Kumar A, Sorensen AG (2008) Investigation of optimizing and translating pH-sensitive pulsed-chemical exchange saturation transfer (CEST) imaging to a 3T clinical scanner. Magn Reson Med 60:834–841CrossRefGoogle Scholar
  12. 12.
    Sun PZ, Benner T, Copen WA, Sorensen AG (2010) Early experience of translating pH-weighted MRI to image human subjects at 3 tesla. Stroke 41:S147–S151CrossRefGoogle Scholar
  13. 13.
    Campbell BC, Mitchell PJ, Kleinig TJ et al (2015) Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 372:1009–1018CrossRefGoogle Scholar
  14. 14.
    Jokivarsi KT, Hiltunen Y, Tuunanen PI, Kauppinen RA, Grohn OH (2010) Correlating tissue outcome with quantitative multiparametric MRI of acute cerebral ischemia in rats. J Cereb Blood Flow Metab 30:415–427CrossRefGoogle Scholar
  15. 15.
    Dani KA, Warach S (2014) Metabolic imaging of ischemic stroke: the present and future. AJNR Am J Neuroradiol 35:S37–S43CrossRefGoogle Scholar
  16. 16.
    Kidwell CS, Saver JL, Mattiello J et al (2000) Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol 47:462–469CrossRefGoogle Scholar
  17. 17.
    Weiss HR, Grayson J, Liu X, Barsoum S, Shah H, Chi OZ (2013) Cerebral ischemia and reperfusion increases the heterogeneity of local oxygen supply/consumption balance. Stroke 44:2553–2558CrossRefGoogle Scholar
  18. 18.
    Tietze A, Blicher J, Mikkelsen IK et al (2014) Assessment of ischemic penumbra in patients with hyperacute stroke using amide proton transfer (APT) chemical exchange saturation transfer (CEST) MRI. NMR Biomed 27:163–174CrossRefGoogle Scholar
  19. 19.
    Kilkenny C, Altman DG (2010) Improving bioscience research reporting: ARRIVE-ing at a solution. Lab Anim 44:377–378CrossRefGoogle Scholar
  20. 20.
    Isayama K, Pitts LH, Nishimura MC (1991) Evaluation of 2,3,5-triphenyltetrazolium chloride staining to delineate rat brain infarcts. Stroke 22:1394–1398CrossRefGoogle Scholar
  21. 21.
    Sun PZ, Farrar CT, Sorensen AG (2007) Correction for artifacts induced by B(0) and B(1) field inhomogeneities in pH-sensitive chemical exchange saturation transfer (CEST) imaging. Magn Reson Med 58:1207–1215CrossRefGoogle Scholar
  22. 22.
    Guivel-Scharen V, Sinnwell T, Wolff SD, Balaban RS (1998) Detection of proton chemical exchange between metabolites and water in biological tissues. J Magn Reson 133:36–45CrossRefGoogle Scholar
  23. 23.
    Keupp J, Baltes C, Harvey P, van den Brink J (2011) Parallel RF transmission based MRI technique for highly sensitive detection of amide proton transfer in the human brain at 3T. In: Proc Intl Soc Mag Reson Med 19Google Scholar
  24. 24.
    Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P (1997) Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 16:187–198CrossRefGoogle Scholar
  25. 25.
    Cox RW (1996) AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 29:162–173CrossRefGoogle Scholar
  26. 26.
    Zhang XY, Wang F, Jin T et al (2017) MR imaging of a novel NOE-mediated magnetization transfer with water in rat brain at 9.4 T. Magn Reson Med 78:588–597CrossRefGoogle Scholar
  27. 27.
    Shen Q, Meng X, Fisher M, Sotak CH, Duong TQ (2003) Pixel-by-pixel spatiotemporal progression of focal ischemia derived using quantitative perfusion and diffusion imaging. J Cereb Blood Flow Metab 23:1479–1488CrossRefGoogle Scholar
  28. 28.
    Leigh R, Knutsson L, Zhou J, van Zijl PC (2017) Imaging the physiological evolution of the ischemic penumbra in acute ischemic stroke. J Cereb Blood Flow Metab 38:1500–1516Google Scholar
  29. 29.
    Harada K, Honmou O, Liu H, Bando M, Houkin K, Kocsis JD (2007) Magnetic resonance lactate and lipid signals in rat brain after middle cerebral artery occlusion model. Brain Res 1134:206–213CrossRefGoogle Scholar
  30. 30.
    Orlowski P, Chappell M, Park CS, Grau V, Payne S (2011) Modelling of pH dynamics in brain cells after stroke. Interface Focus 1:408–416CrossRefGoogle Scholar
  31. 31.
    Lee D, Zhao X, Heo H, Zhang Y, Jiang S, Zhou J (2016) Dynamic changes of amide proton transfer (APT) and multi-parametric MR signals in transient focal ischemia in rats. In: Proc 24th Annual Meeting ISMRM SingaporeGoogle Scholar
  32. 32.
    An HY, Ford AL, Chen YS et al (2015) Defining the ischemic penumbra using magnetic resonance oxygen metabolic index. Stroke 46:982–988CrossRefGoogle Scholar
  33. 33.
    Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J (2007) Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology 49:93–102CrossRefGoogle Scholar
  34. 34.
    Bivard A, Krishnamurthy V, Stanwell P et al (2014) Spectroscopy of reperfused tissue after stroke reveals heightened metabolism in patients with good clinical outcomes. J Cereb Blood Flow Metab 34:1944–1950CrossRefGoogle Scholar
  35. 35.
    Wey HY, Desai VR, Duong TQ (2013) A review of current imaging methods used in stroke research. Neurol Res 35:1092–1102CrossRefGoogle Scholar
  36. 36.
    Obrenovitch TP (1995) The ischaemic penumbra: twenty years on. Cerebrovasc Brain Metab Rev 7:297–323PubMedGoogle Scholar
  37. 37.
    Thornton JS, Ordidge RJ, Penrice J et al (1998) Temporal and anatomical variations of brain water apparent diffusion coefficient in perinatal cerebral hypoxic-ischemic injury: relationships to cerebral energy metabolism. Magn Reson Med 39:920–927CrossRefGoogle Scholar
  38. 38.
    Xue R, Sawada M, Goto S et al (2001) Rapid three-dimensional diffusion MRI facilitates the study of acute stroke in mice. Magn Reson Med 46:183–188CrossRefGoogle Scholar
  39. 39.
    Dijkhuizen RM, Knollema S, van der Worp HB et al (1998) Dynamics of cerebral tissue injury and perfusion after temporary hypoxia-ischemia in the rat: evidence for region-specific sensitivity and delayed damage. Stroke 29:695–704CrossRefGoogle Scholar
  40. 40.
    Yamasaki F, Takaba J, Ohtaki M et al (2005) Detection and differentiation of lactate and lipids by single-voxel proton MR spectroscopy. Neurosurg Rev 28:267–277CrossRefGoogle Scholar
  41. 41.
    Heo HY, Zhang Y, Lee DH, Hong X, Zhou J (2016) Quantitative assessment of amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging with extrapolated semi-solid magnetization transfer reference (EMR) signals: application to a rat glioma model at 4.7 tesla. Magn Reson Med 75:137–149CrossRefGoogle Scholar
  42. 42.
    Heo HY, Zhang Y, Jiang S, Lee DH, Zhou J (2016) Quantitative assessment of amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging with extrapolated semisolid magnetization transfer reference (EMR) signals: II. Comparison of three EMR models and application to human brain glioma at 3 tesla. Magn Reson Med 75:1630–1639CrossRefGoogle Scholar
  43. 43.
    Dula AN, Smith SA, Gore JC (2013) Application of chemical exchange saturation transfer (CEST) MRI for endogenous contrast at 7 tesla. J Neuroimaging 23:526–532CrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2019

Authors and Affiliations

  1. 1.Department of Radiology and Research Institute of RadiologyUniversity of Ulsan College of MedicineSeoulSouth Korea
  2. 2.Asan Institute for Life SciencesAsan Medical CenterSeoulSouth Korea
  3. 3.University of Ulsan College of Medicine, Asan Medical CenterSeoulSouth Korea

Personalised recommendations