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A Multi-Ligand Imaging Study Exploring GABAergic Receptor Expression and Inflammation in Multiple Sclerosis

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Abstract

Purpose

The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABAA binding and the innate immune response is explored using positron emission tomography (PET) with [11C] flumazenil (FMZ) and [11C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages.

Procedures

Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABAA receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function. A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest.

Results

GABAA receptor binding was higher throughout the cortex in MS patients (5.72 ± 0.91) as compared with HC (4.70 ± 0.41) (p = 0.002). A significant correlation was found between FMZ binding and PK-PET within the cortex (r = 0.61, p < 0.001) and among the occipital (r = 0.61, p = 0.012), parietal (r = 0.49, p = 0.041), and cingulate (r = 0.32, p = 0.006) regions.

Conclusions

A higher GABAA receptor density in MS subjects compared with HC was observed and correlated with innate immune activity. Our observations demonstrate that immune-driven GABAergic abnormalities may be present in MS.

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Acknowledgments

The authors are grateful to the professional staff at the Citigroup Biomedical Imaging Center of Weill Cornell Medical College, including, in alphabetical order, John W. Babich PhD, Jonathan Dyke PhD, Simon Morim, Amelia Ng, and Nelsie Pastrano-Redula. The authors also want to acknowledge Sneha Pandya and David Schlyer PhD for advisement on data analysis. The authors further acknowledge Sudhin A. Shah PhD with regard to health control subject recruitment and data sharing. The authors acknowledge Leorah Freeman MD for her thoughtful review of the manuscript. This conduct of the research was supported by in part through an investigator-initiated study supported by Biogen and the Weill Cornell Clinical and Translational Science Center (CTSC).

Funding

This work was supported by in part through an investigator-initiated study supported by Biogen Cambridge MA. (grant # 55000025) and from the Weill Cornell Clinical and Translational Science Center (CTSC), New York, NY (grant UL1 TR000456-06).

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Authors and Affiliations

  1. Department of Radiology, Weill Cornell Medicine, New York, NY, 10021, USA

    Yeona Kang, Wenchao Qu, Paresh J. Kothari, Amy Kuceyeski & Susan A. Gauthier

  2. Department of Mathematics, Howard University, Washington, D.C, 20059, USA

    Yeona Kang

  3. Department of Mathematics and Statistics, College of Science and Health Professions, Cleveland State University, Cleveland, OH, 44115, USA

    Sandra Milena Hurtado Rúa

  4. Department of Neurology, Judith Jaffe Multiple Sclerosis Center, Weill Cornell Medicine, New York, NY, 10021, USA

    Ulrike W. Kaunzner, Jai Perumal, Nancy Nealon, Timothy Vartanian & Susan A. Gauthier

  5. Feil Family Brain and Mind Institute, Weill Cornell, New York, NY, 10021, USA

    Timothy Vartanian, Amy Kuceyeski & Susan A. Gauthier

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  1. Yeona Kang
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Correspondence to Susan A. Gauthier.

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Conflict of Interest

Dr. Kang reports no disclosures. Dr. Kaunzner reports no disclosures. Dr. Perumal reports no disclosures. Dr. Nealon reports no disclosures. Dr. Perumal has received consultant fees from Genzyme. Dr. Kothari reports no disclosures. Dr. Vartanian has received consultant fees from Biogen, Norvartis, and Genzyme as well as Celgene. Dr. Kuceyeski reports no disclosures. Hurtado Rúa reports no disclosures. Dr. Gauthier has grant support from Genzyme, Genentech, and Mallinckrodt and has also received consulting fees from Biogen, Genetech, and Celgene.

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Supplement Fig. 1

Illustrate time activity curves of Pons with MS patients and HC. There is no significant difference in any time points. (JPG 39 kb)

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Kang, Y., Rúa, S.M.H., Kaunzner, U.W. et al. A Multi-Ligand Imaging Study Exploring GABAergic Receptor Expression and Inflammation in Multiple Sclerosis. Mol Imaging Biol 22, 1600–1608 (2020). https://doi.org/10.1007/s11307-020-01501-z

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