Skip to main content
SpringerLink
Log in

Spatiotemporal Dynamics of Neuroinflammation Relate to Behavioral Recovery in Rats with Spinal Cord Injury

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The degree and dynamic progression of neuroinflammation after traumatic spinal cord injuries (SCI) are crucial determinants of the severity of injury and potential for recovery. We used Positron Emission Tomography (PET) to monitor neuroinflammation longitudinally, correlating it with Chemical Exchange Saturation Transfer (CEST) Magnetic Resonance Imaging (MRI) and behavior in contusion-injured rats. These studies help validate CEST metrics and confirm how imaging may be used to evaluate the efficacy of therapies and understand their mechanisms of action.

Procedures

12 SCI and 4 sham surgery rats were subjected to CEST MRI and PET-Translocator Protein (TSPO) scans for 8 weeks following injury. Z-spectra from the SCI were analyzed using a 5-Lorentzian pool model for fitting. Weekly motor and somatosensory behavior were correlated with imaging metrics, which were validated through post-mortem histological and immuo-staining using ionized calcium-binding adaptor protein-1 (iba-1, microglia) and glial fibrillary acidic protein (GFAP, astrocytes).

Results

PET-TSPO showed widespread inflammation and post-mortem histology confirmed the presence of activated microglia. Changes in CEST and nuclear Overhauser Effect (NOE) peaks at 3.5 ppm and -1.6 ppm respectively were largest within the first week after injury and more pronounced in rostral versus caudal segments. These temporal indices of neuroinflammation corresponded to the recovery of locomotor behaviors and somatic sensation in rats with moderate contusion injury. The results confirm that CEST MRI metrics are sensitive indices of states of neuroinflammation within injured spinal cords.

Conclusions

The detection of dynamic spatiotemporal features of neuroinflammation progression underscores the importance of considering their timings and locations for neuroprotective and anti-inflammatory therapies. The availability of noninvasive MRI indices of neuroinflammation may facilitate clinical trials aimed at treatments that promote recovery after SCI.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

Data availability

The datasets acquired from the study and analysis code used are available from the corresponding author upon reasonable request.

References

  1. Silva NA, Sousa N, Reis RL, Salgado AJ (2014) From basics to clinical: A comprehensive review on spinal cord injury. Prog Neurobiol 114:25–57. https://doi.org/10.1016/j.pneurobio.2013.11.002

    Article  PubMed  Google Scholar 

  2. Sweis R, Biller J (2017) Systemic Complications of Spinal Cord Injury. Curr Neurol Neurosci Rep 17:1–8

    Article  Google Scholar 

  3. Profyris C, Cheema SS, Zang DW et al (2004) Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Dis 15:415–436. https://doi.org/10.1016/J.NBD.2003.11.015

    Article  PubMed  Google Scholar 

  4. Badhiwala JH, Ahuja CS, Fehlings MG (2019) Time is spine: A review of translational advances in spinal cord injury. J Neurosurg Spine 30:1–18

    Article  Google Scholar 

  5. Stammers AT, Liu J, Kwon BK (2012) Expression of inflammatory cytokines following acute spinal cord injury in a rodent model. J Neurosci Res 90:782–790. https://doi.org/10.1002/JNR.22820

    Article  CAS  PubMed  Google Scholar 

  6. Cohen-Adad J, El Mendili M-M, Lehéricy S et al (2011) Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI. Neuroimage 55:1024–1033. https://doi.org/10.1016/J.NEUROIMAGE.2010.11.089

    Article  CAS  PubMed  Google Scholar 

  7. Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49:377–391

    Article  CAS  PubMed  Google Scholar 

  8. Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617–627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. van Zijl PCM, Yadav NN (2011) Chemical exchange saturation transfer (CEST): what is in a name and what isn’t? Magnetic Resonance in Medicine 65(4):927–948. https://doi.org/10.1002/mrm.22761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang F, Qi HX, Zu Z et al (2015) Multiparametric MRI reveals dynamic changes in molecular signatures of injured spinal cord in monkeys. Magn Reson Med 74:1125–1137. https://doi.org/10.1002/mrm.25488

    Article  PubMed  Google Scholar 

  11. Wang F, Zu Z, Wu R et al (2018) MRI evaluation of regional and longitudinal changes in Z-spectra of injured spinal cord of monkeys. Magn Reson Med 79:1070–1082. https://doi.org/10.1002/mrm.26756

    Article  PubMed  Google Scholar 

  12. Wu TL, Byun NE, Wang F et al (2020) Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion, quantitative magnetization transfer and functional magnetic resonance imaging. NMR Biomed 33:e4216. https://doi.org/10.1002/NBM.4216

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhou J, Heo HY, Knutsson L et al (2019) APT-weighted MRI: Techniques, current neuro applications, and challenging issues. J Magn Reson Imaging 50:347–364. https://doi.org/10.1002/JMRI.26645

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang XY, Wang F, Afzal A et al (2016) A new NOE-mediated MT signal at around -1.6 ppm for detecting ischemic stroke in rat brain. Magn Reson Imaging 34:1100–1106. https://doi.org/10.1016/j.mri.2016.05.002

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tremoleda JL, Thau-Zuchman O, Davies M et al (2016) In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [18F]GE-180 and effect of docosahexaenoic acid. Eur J Nucl Med Mol Imaging 43:1710–1722. https://doi.org/10.1007/s00259-016-3391-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Narayanaswami V, Dahl K, Bernard-Gauthier V et al (2018) Emerging PET radiotracers and targets for imaging of neuroinflammation in neurodegenerative diseases: Outlook beyond TSPO. Molecular Imaging 2018;17. https://doi.org/10.1177/1536012118792317

    Article  CAS  Google Scholar 

  17. Werry EL, Bright FM, Piguet O et al (2019) Recent Developments in TSPO PET Imaging as A Biomarker of Neuroinflammation in Neurodegenerative Disorders. Int J Mol Sci 20:3161. https://doi.org/10.3390/IJMS20133161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lu M, Drake G, Wang F et al (2021) Design and construction of an interchangeable RF coil system for rodent spinal cord MR imaging at 9.4 T. Magn Reson Imaging 84:124–131. https://doi.org/10.1016/j.mri.2021.09.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. O’Haver T (2008) peakfit.m

  20. Cheung YY, Nickels ML, Tang D et al (2014) Facile synthesis of SSR180575 and discovery of 7-chloro-N, N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer. Bioorg Med Chem Lett 24:4466–4471. https://doi.org/10.1016/J.BMCL.2014.07.091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fouad K, Ng C, Basso DM (2020) Behavioral testing in animal models of spinal cord injury. Exp Neurol 333:113410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Deuis JR, Dvorakova LS, Vetter I (2017) Methods Used to Evaluate Pain Behaviors in Rodents. Front Mol Neurosci 10:284. https://doi.org/10.3389/fnmol.2017.00284

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bankhead P, Loughrey MB, Fernández JA et al (2017) (2017) QuPath: Open source software for digital pathology image analysis. Sci Rep 71(7):1–7. https://doi.org/10.1038/s41598-017-17204-5

    Article  CAS  Google Scholar 

  24. Liu D, Thangnipon W, McAdoo DJ (1991) Excitatory amino acids rise to toxic levels upon impact injury to the rat spinal cord. Brain Res 547:344–348. https://doi.org/10.1016/0006-8993(91)90984-4

    Article  CAS  PubMed  Google Scholar 

  25. Iizuka H, Yamamoto H, Iwasaki Y, Konno H (1987) Evolution of tissue damage in compressive spinal cord injury in rats. J Neurosurg 66:595–603. https://doi.org/10.3171/JNS.1987.66.4.0595

    Article  CAS  PubMed  Google Scholar 

  26. 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 27:163–174. https://doi.org/10.1002/nbm.3048

    Article  PubMed  Google Scholar 

  27. Jones CK, Schlosser MJ, van Zijl PCM et al (2006) Amide proton transfer imaging of human brain tumors at 3T. Magn Reson Med 56:585–592. https://doi.org/10.1002/mrm.20989

    Article  PubMed  Google Scholar 

  28. Zhang H, Wang W, Jiang S et al (2017) Amide proton transfer-weighted MRI detection of traumatic brain injury in rats. J Cereb Blood Flow Metab 37:3422–3432. https://doi.org/10.1177/0271678X17690165/ASSET/IMAGES/LARGE/10.1177_0271678X17690165-FIG1.JPEG

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dong Y, Gu Y, Lu J et al (2022) Amide Proton Transfer-Weighted Magnetic Resonance Imaging for Detecting Severity and Predicting Outcome after Traumatic Brain Injury in Rats. Neurotrauma Reports 3:261–275. https://doi.org/10.1089/NEUR.2021.0064/ASSET/IMAGES/LARGE/NEUR.2021.0064_FIGURE7.JPEG

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dickens AM, Vainio S, Marjamäki P et al (2014) Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med 55:466–472. https://doi.org/10.2967/JNUMED.113.125625

    Article  CAS  PubMed  Google Scholar 

  31. Lavisse S, Guillermier M, Hérard AS et al (2012) Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging. J Neurosci 32:10809–10818. https://doi.org/10.1523/JNEUROSCI.1487-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Toossi A, Bergin B, Marefatallah M et al (2021) (2021) Comparative neuroanatomy of the lumbosacral spinal cord of the rat, cat, pig, monkey, and human. Sci Reports 111(11):1–15. https://doi.org/10.1038/s41598-021-81371-9

    Article  CAS  Google Scholar 

  33. Kim J, Wu Y, Guo Y et al (2015) A review of optimization and quantification techniques for chemical exchange saturation transfer MRI toward sensitive in vivo imaging. Contrast Med Mol Imaging 10:163–178. https://doi.org/10.1002/CMMI.1628

    Article  CAS  Google Scholar 

  34. Duan W, Huang Q, Chen Z et al (2019) Comparisons of motor and sensory abnormalities after lumbar and thoracic contusion spinal cord injury in male rats. Neurosci Lett 708:134358. https://doi.org/10.1016/J.NEULET.2019.134358

    Article  CAS  PubMed  Google Scholar 

  35. Gaudet AD, Ayala MT, Schleicher WE et al (2017) Exploring acute-to-chronic neuropathic pain in rats after contusion spinal cord injury. Exp Neurol 295:46–54. https://doi.org/10.1016/J.EXPNEUROL.2017.05.011

    Article  PubMed  Google Scholar 

  36. Cai K, Haris M, Singh A et al (2012) Magnetic resonance imaging of glutamate. Nat Med 182(18):302–306. https://doi.org/10.1038/nm.2615

    Article  CAS  Google Scholar 

  37. By S, Barry RL, Smith AK et al (2018) Amide proton transfer CEST of the cervical spinal cord in multiple sclerosis patients at 3T. Magn Reson Med 79:806–814. https://doi.org/10.1002/MRM.26736

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study is supported by DOD Grant SC190134 (awarded to LMC) and acknowledges the support also of NIH award 1 S10 OD025085 (awarded to JCG). We acknowledge additional NIH support for instrumentation 1S10OD016245-01 and 1 S10RR023784-01. The authors gratefully acknowledge Zou Yue and Chaohui Tang for their assistance with surgical procedures and perfusion of animals, Drs. Yiu-Yin Cheung and Fei Liu and Radiochemistry core for radiotracer production, the Center for Small Animal Imaging (CSAI) staff for imaging support, and the Vanderbilt University Medical Center (VUMC) Translational Pathology Shared Resource Core (NCI/NIH Cancer Center Support Grant 2P30 CA068485-14) for their expertise with processing the spinal cord tissue histology.

Author information

Author notes

  1. John C. Gore and Li Min Chen are equally responsible for the project.

Authors and Affiliations

  1. Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, USA

    Chaoqi Mu, Jamie L. Reed, Feng Wang, M. Noor Tantawy, John C. Gore & Li Min Chen

  2. Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Chaoqi Mu, Jamie L. Reed, Feng Wang, M. Noor Tantawy, John C. Gore & Li Min Chen

  3. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA

    Chaoqi Mu, John C. Gore & Li Min Chen

Authors
  1. Chaoqi Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jamie L. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Noor Tantawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John C. Gore
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Min Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Min Chen.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The manuscript has been submitted for review and approved for submission by all of the named co-authors.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 6628 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mu, C., Reed, J.L., Wang, F. et al. Spatiotemporal Dynamics of Neuroinflammation Relate to Behavioral Recovery in Rats with Spinal Cord Injury. Mol Imaging Biol 26, 240–252 (2024). https://doi.org/10.1007/s11307-023-01875-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-023-01875-w

Keywords

Search

Navigation