Skip to main content
SpringerLink
Log in

A pilot study to assess blood-brain barrier permeability in long COVID

  • Research
  • Published:
Brain Imaging and Behavior Aims and scope Submit manuscript

Abstract

The etiology of brain fog associated with long COVID is not clear. Based on some preliminary work, disruption of the blood-brain barrier has been hypothesized, but has not been tested in patients with long COVID. In this case-control pilot study, we evaluated blood-brain barrier permeability in patients with long COVID and subjective memory loss or brain fog. We used 99 m Technetium diethylenetriaminepentaacetic acid single-photon emission computed tomography (SPECT) to measure blood-brain barrier permeability and a telephone assessment (T-cog) to measure cognitive function. The blood-brain barrier permeability was quantified via SPECT standard uptake value (SUV). We assessed the blood-brain barrier permeability in 14 long COVID patients and 10 control participants without subjective cognitive impairment or brain fog. Participants in the two groups were similar in age. The long COVID group had more comorbidities compared to the control group. There was no difference in the SUVs in the long COVID (0.22 ± 0.12) vs the control (0.17 ± 0.04) group. There was no difference in the T-cog results in the two groups either. We found no evidence of a difference in blood-brain permeability in patients with long COVID when compared to controls without a known history of COVID-19 infection. Larger studies are needed to confirm these findings.

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

Similar content being viewed by others

Data availability

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  • Bonetto, V., Pasetto, L., Lisi, I., Carbonara, M., Zangari, R., Ferrari, E., Punzi, V., Luotti, S., Bottino, N., Biagianti, B., Moglia, C., Fuda, G., Gualtierotti, R., Blasi, F., Canetta, C., Montano, N., Tettamanti, M., Camera, G., Grimoldi, M., ... Zanier, E. R. (2022). Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations. Frontiers in Immunology, 13, 1070379. https://doi.org/10.3389/fimmu.2022.1070379

  • Chagnot, A., Barnes, S. R., & Montagne, A. (2021). Magnetic resonance imaging of blood-brain barrier permeability in dementia. Neuroscience, 474, 14–29. https://doi.org/10.1016/j.neuroscience.2021.08.003

    Article  CAS  PubMed  Google Scholar 

  • Crunfli, F., Carregari, V. C., Veras, F. P., Silva, L. S., Nogueira, M. H., Antunes, A., Vendramini, P. H., Valença, A. G. F., Brandão-Teles, C., Zuccoli, G. D. S., Reis-de-Oliveira, G., Silva-Costa, L. C., Saia-Cereda, V. M., Smith, B. J., Codo, A. C., de Souza, G. F., Muraro, S. P., Parise, P. L., Toledo-Teixeira, D. A., ... Martins-de-Souza, D. (2022). Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. Proceedings of the National Academy of Sciences of the United States of America, 119(35), e2200960119. https://doi.org/10.1073/pnas.2200960119

  • Douaud, G., Lee, S., Alfaro-Almagro, F., Arthofer, C., Wang, C., McCarthy, P., Lange, F., Andersson, J. L. R., Griffanti, L., Duff, E., Jbabdi, S., Taschler, B., Keating, P., Winkler, A. M., Collins, R., Matthews, P. M., Allen, N., Miller, K. L., Nichols, T. E., & Smith, S. M. (2022). SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature, 604(7907), 697–707. https://doi.org/10.1038/s41586-022-04569-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilad, R., Lampl, Y., Eilam, A., Boaz, M., & Loyberboim, M. (2012). SPECT-DTPA as a tool for evaluating the blood-brain barrier in post-stroke seizures. Journal of Neurology, 259(10), 2041–2044. https://doi.org/10.1007/s00415-012-6445-2

    Article  CAS  PubMed  Google Scholar 

  • Gupta, A., Bansal, A., Young, K., Gautam, A., Donald, J., Comfort, B., & Montgomery, R. (2023). Blood–Brain Barrier Permeability in ESKD—A Proof-of-Concept Study. Journal of the American Society of Nephrology. https://doi.org/10.1681/ASN.0000000000000167

  • Kanda, T., Fukusato, T., Matsuda, M., Toyoda, K., Oba, H., Kotoku, J., Haruyama, T., Kitajima, K., & Furui, S. (2015). Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: Evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology, 276(1), 228–232. https://doi.org/10.1148/radiol.2015142690

    Article  PubMed  Google Scholar 

  • Kempuraj, D., Aenlle, K. K., Cohen, J., Mathew, A., Isler, D., Pangeni, R. P., Nathanson, L., Theoharides, T. C., & Klimas, N. G. (2023). COVID-19 and long COVID: Disruption of the neurovascular unit, blood-brain barrier, and tight junctions. Neuroscientist, 10738584231194927. https://doi.org/10.1177/10738584231194927

  • Krasemann, S., Haferkamp, U., Pfefferle, S., Woo, M. S., Heinrich, F., Schweizer, M., Appelt-Menzel, A., Cubukova, A., Barenberg, J., Leu, J., Hartmann, K., Thies, E., Littau, J. L., Sepulveda-Falla, D., Zhang, L., Ton, K., Liang, Y., Matschke, J., Ricklefs, F., ... Pless, O. (2022). The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Reports, 17(2), 307–320. https://doi.org/10.1016/j.stemcr.2021.12.011

  • Lee, M. H., Perl, D. P., Steiner, J., Pasternack, N., Li, W., Maric, D., Safavi, F., Horkayne-Szakaly, I., Jones, R., Stram, M. N., Moncur, J. T., Hefti, M., Folkerth, R. D., & Nath, A. (2022). Neurovascular injury with complement activation and inflammation in COVID-19. Brain, 145(7), 2555–2568. https://doi.org/10.1093/brain/awac151

    Article  PubMed  Google Scholar 

  • Liu, Y.-H., Chen, Y., Wang, Q.-H., Wang, L.-R., Jiang, L., Yang, Y., Chen, X., Li, Y., Cen, Y., Xu, C., Zhu, J., Li, W., Wang, Y.-R., Zhang, L.-L., Liu, J., Xu, Z.-Q., & Wang, Y.-J. (2022). One-year trajectory of cognitive changes in older survivors of COVID-19 in Wuhan, China: A longitudinal cohort study. JAMA Neurology, 79(5), 509–517. https://doi.org/10.1001/jamaneurol.2022.0461

    Article  PubMed  PubMed Central  Google Scholar 

  • Lorberboym, M., Lampl, Y., & Sadeh, M. (2003). Correlation of 99mTc-DTPA SPECT of the blood-brain barrier with neurologic outcome after acute stroke. Journal of Nuclear Medicine, 44(12), 1898–1904.

    PubMed  Google Scholar 

  • Matschke, J., Lütgehetmann, M., Hagel, C., Sperhake, J. P., Schröder, A. S., Edler, C., Mushumba, H., Fitzek, A., Allweiss, L., Dandri, M., Dottermusch, M., Heinemann, A., Pfefferle, S., Schwabenland, M., Sumner Magruder, D., Bonn, S., Prinz, M., Gerloff, C., Püschel, K., ... Glatzel, M. (2020). Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. The Lancet Neurology, 19(11), 919–929. https://doi.org/10.1016/S1474-4422(20)30308-2

  • Nation, D. A., Sweeney, M. D., Montagne, A., Sagare, A. P., D'Orazio, L. M., Pachicano, M., Sepehrband, F., Nelson, A. R., Buennagel, D. P., Harrington, M. G., Benzinger, T. L. S., Fagan, A. M., Ringman, J. M., Schneider, L. S., Morris, J. C., Chui, H. C., Law, M., Toga, A. W., & Zlokovic, B. V. (2019). Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature Medicine, 25(2), 270–276. https://doi.org/10.1038/s41591-018-0297-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolen, L. T., Mukerji, S. S., & Mejia, N. I. (2022). Post-acute neurological consequences of COVID-19: An unequal burden. Nature Medicine, 28(1), 20–23. https://doi.org/10.1038/s41591-021-01647-5

    Article  CAS  PubMed  Google Scholar 

  • Starr, J. M., Wardlaw, J., Ferguson, K., MacLullich, A., Deary, I. J., & Marshall, I. (2003). Increased blood-brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. Journal of Neurology, Neurosurgery, and Psychiatry, 74(1), 70–76. https://doi.org/10.1136/jnnp.74.1.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stein, S. R., Ramelli, S. C., Grazioli, A., Chung, J.-Y., Singh, M., Yinda, C. K., Winkler, C. W., Sun, J., Dickey, J. M., Ylaya, K., Ko, S. H., Platt, A. P., Burbelo, P. D., Quezado, M., Pittaluga, S., Purcell, M., Munster, V. J., Belinky, F., Ramos-Benitez, M. J., ... Consortium, N. C.-A. (2022). SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature, 612(7941), 758–763. https://doi.org/10.1038/s41586-022-05542-y

  • Venkataramani, V., & Winkler, F. (2022). Cognitive deficits in long Covid-19. The New England Journal of Medicine, 387(19), 1813–1815. https://doi.org/10.1056/NEJMcibr2210069

    Article  CAS  PubMed  Google Scholar 

  • Zingaropoli, M. A., Iannetta, M., Piermatteo, L., Pasculli, P., Latronico, T., Mazzuti, L., Campogiani, L., Duca, L., Ferraguti, G., De Michele, M., Galardo, G., Pugliese, F., Antonelli, G., Andreoni, M., Sarmati, L., Lichtner, M., Turriziani, O., Ceccherini-Silberstein, F., Liuzzi, G. M., ... Ciardi, M. R. (2022). Neuro-axonal damage and alteration of blood-brain barrier integrity in COVID-19 patients. Cells, 11(16). https://doi.org/10.3390/cells11162480

Download references

Acknowledgements

We acknowledge the research coordinator Jessica Reed and the study participants.

Funding

This research was funded by the NIH K23AG055666 and University of Kansas Medical Center clinical pilot grant awarded to A. Gupta.

Author information

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA

    Aditi Gupta & Branden Comfort

  2. Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA

    Aditi Gupta

  3. Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, USA

    Kate Young & Robert Montgomery

Authors
  1. Aditi Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Branden Comfort
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kate Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert Montgomery
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, A. Gupta; methodology, A. Gupta and B. Comfort; formal analysis, R. Montgomery and K. Young; writing—original draft preparation, A. Gupta; writing—review and editing, B. Comfort, R. Montgomery, and K. Young; funding acquisition, A. Gupta. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Aditi Gupta.

Ethics declarations

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the University of Kansas Medical Center (STUDY0014699 and approved on 3/18/2021).

Consent to participate

Informed consent was obtained from all subjects involved in the study.

Consent for publication

All authors have read and consent to the published version of the manuscript.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

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

Supplementary Information

ESM 1

(DOCX 47 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

Gupta, A., Comfort, B., Young, K. et al. A pilot study to assess blood-brain barrier permeability in long COVID. Brain Imaging and Behavior (2024). https://doi.org/10.1007/s11682-024-00877-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11682-024-00877-8

Keywords

Search

Navigation